Imidazo-oxadiazole and imidazo-thiadiazole derivatives

ABSTRACT

The present invention provides compounds of Formula (I) used as Amyloid beta lowering agent for the treatment of neurodegenerative diseases.

The present invention provides imidazo-oxadiazole andimidazo-thiadiazole derivatives useful as amyloid-beta lowering agents.The invention further relates to processes for preparing such compounds,pharmaceutical compositions comprising said compounds and their use inthe treatment of amyloidosis and neurodegenerative diseases that includebut are not limited to Alzheimer's disease and Down's Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a progressive neurodegenerative disordermarked by loss of memory, cognition, and behavioral stability. ADafflicts 6-10% of the population over age 65 and up to 50% over age 85.It is the leading cause of dementia and the third leading cause of deathafter cardiovascular disease and cancer. At present, there are noeffective treatments for AD and treatment is limited to the use ofsymptomatic agents such as the cholinesterase inhibitor, donepezil(Aricept®, Pfizer). The total net cost related to AD in the U.S. exceeds$100 billion annually.

AD is characterised pathologically by the presence of specific lesionsin the limbic and cortical regions of the brain. These includeintracellular neurofibrillary tangles consisting of hyperphosphorylatedtau protein and the extracellular deposition of fibrillar aggregates ofamyloid-beta peptides in the form of amyloid plaques (senile plaques).The major components of amyloid plaques are amyloid-beta (A-beta, Abetaor Aβ) peptides of various lengths (39-42 amino acids). A variantthereof, which is the Aβ1-42 (Abeta1-42, Aβ42) peptide, is believed tobe the major pathogenic species in AD brain and can act as a seed foramyloid plaque formation. Another variant is the Aβ1-40 (Abeta1-40,Aβ40) peptide.

The identification of mutations in the beta-Amyloid Precursor Protein(beta-APP, β-APP or APP), Presenilin-1 (PS-1) and Presenilin-2 (PS-2)genes that increase Aβ production and lead to early-onset familial formsof AD have given strong support to the “amyloid cascade hypothesis” ofAD (Hardy, 2006 Curr Alzheimer Res. 3(1):71-73; Tanzi and Bertram, 2005Cell 120, 545-555) and therapeutic approaches targeting Aβ production.

There is emerging data on the role of Aβ peptides in other diseasesincluding, but not limited to Down's syndrome (DS), mild cognitiveimpairment (MCI), cerebral amyloid angiopathy (CAA), inclusion bodymyositis (IBM) and age-related macular degeneration. Hence, Aβ loweringagents could be beneficial for the treatment of diverse pathologies inwhich Aβ peptides are implicated. Aβ peptides are generated followingproteolytic processing of APP. The generation of Aβ peptides isregulated by at least two proteolytic activities referred to as β-siteAPP cleaving enzyme 1 (BACE-1) and γ-secretase. APP is initially cleavedby BACE-1 at the N-terminus (Met-Asp bond) of the Aβ domain leading tothe secretion of soluble APPβ (sAPPβ) and the retention of a 12 kDamembrane-bound carboxy terminal fragment (CTF3). The latter issubsequently cleaved by γ-secretase to generate Aβ peptides of varyinglength and an APP intracellular domain (AICD).

BACE-1 is a type I transmembrane aspartic protease that comprises alarge extracellular domain containing the catalytic active site, asingle transmembrane domain and a short cytoplasmic tail [Hussain et al.1999 Mol. Cell Neurosci. 14(6):419-427]. The γ-secretase activityresides within a multiprotein complex containing at least fourcomponents: a presenilin (PS) heterodimer, nicastrin, anteriorpharynx-defective 1 (Aph-1) and presenilin enhancer 2 (Pen-2). The PSheterodimer consists of the amino- and carboxy terminal fragmentsgenerated by endoproteolysis of PS and the two aspartates in thecatalytic site are at the interface of this heterodimer.

Therapeutic approaches to lower Aβ production include but are notrestricted to inhibition or modulation of BACE-1 and γ-secretaseactivity (Albert, 2009 Prog Med Chem. 48: 133-61; Beher, 2008 Curr TopMed Chem. 8: 34-37; Panza et al. 2011 Curr Med Chem. 18(35): 5430-5447).However, due to the fundamental role γ-secretase plays in theintramembrane proteolysis of other proteins, the clinical development ofγ-secretase inhibitors was hindered by mechanism-based toxicities(Schor, 2011 Ann Neurol. 69: 237-239).

There is a strong need for novel compounds which decrease Aβ productionthereby opening new avenues for the treatment of AD. It is an object ofthe present invention to provide such novel compounds.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I)

Wherein

X denotes O or S,

U is selected from

-   -   (i) a phenyl ring which may be substituted by 1 or 2 groups        independently selected from C₁-C₆-alkoxy, C₁-C₆-alkyl, halogen,        CN    -   (ii) a 5- or 6-membered unsaturated or aromatic heterocyclic        system comprising 1 nitrogen atom and optionally up to 2        additional heteroatoms independently selected from N, O or S,        which may be substituted by 1 or 2 groups independently selected        from C₁-C₆-alkoxy, C₁-C₆-alkyl, halogen, CN,    -   (iii) a single bond.

T denotes —NR⁵—, —NR⁵CO—, —CONR⁵, —NR⁵—CO—NR⁵, —CO—

W is selected from

-   -   (i) a linear or branched C₁-C₆-alkylene wherein 1 to 2 H atoms        may be replaced by a phenyl ring, halogen, CN, CF₃,    -   (ii) a linear or branched C₁-C₆-alkylene wherein 1 CH₂ group is        replaced by a 3- to 7-membered saturated carbocyclic ring,    -   (iii) a linear or branched C₁-C₆-alkylene wherein 1 CH₂ group is        replaced by        -   a phenyl ring optionally fused with the phenyl ring A,        -   a 5- or 6-membered saturated heterocyclic system containing            1 or 2 nitrogen atoms, or        -   a 5-membered aromatic heterocyclic system containing 1 to 3            heteroatoms independently selected from N, O and S, and            optionally fused with a saturated 6-membered carbocyclic            ring, or optionally fused with the phenyl ring A,        -   and wherein another CH₂ group which is not linked to T is            optionally replaced by —O— or NR⁵.    -   (iv) a single bond,

R⁵ is H or a linear or branched C₁-C₆-alkyl,

R¹ denotes a linear or branched alkyl having 1 to 6 carbon atoms.

R^(a) denotes H, CN, halogen, a linear or branched alkyl having 1 to 6carbon atoms, wherein 1 to 3 H atoms may be replaced by halogens, linearor branched alkoxy having 1 to 6 carbon atoms, wherein 1 to 3 H atomsmay be replaced by halogens,

R², R³, R⁴ are independently from one another selected from CN, halogen,a linear or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 3 Hatoms may be replaced by halogens, linear or branched alkoxy having 1 to6 carbon atoms, wherein 1 to 3 H atoms may be replaced by halogens, Aswell as pharmaceutically acceptable derivatives, solvates, tautomers,salts, hydrates and stereoisomers thereof, including mixtures thereof inall ratios.

When a substituent is mentioned several times in a group, like R⁵ in T,each of the substitutent independently takes the meaning given above.

The present invention further relates to a set or a kit consisting ofseparate packs of

-   -   (a) an effective amount of a compound according to Formula (I)        or related Formulae and/or pharmaceutically usable derivatives,        tautomers, salts, solvates and stereoisomers thereof, including        mixtures thereof in all ratios,        -   and    -   (b) an effective amount of a further medicament active        ingredient.

In a preferred embodiment, U in the compounds of Formula (I) is selectedfrom the following groups:

In another embodiment, U is single bond.

In another embodiment, W in Formula (I) denotes one of the followinggroups:

Alternatively, the group W-A denotes one of the following groups:

The preferred compounds of the present invention are the following:

Ex. No Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

The following abbreviations refer respectively to the definitions below:

aq (aqueous), h (hour), g (gram), L (litre), mg (milligram), MHz(Megahertz), μM (micromolar), min (minute), mm (millimeter), mmol(millimole), mM (millimolar), m.p. (melting point), eq (equivalent), mL(millilitre), μL (microlitre), ACN (acetonitrile), BINAP(2,2′-bis(disphenylphosphino)-1,1′-binaphthalene), BOC(tert-butoxy-carbonyl), CBZ (carbobenzoxy), CDCl3 (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DABAL-Me₃(Bis(trimethylaluminum)-1,4-diazabicyclo(2.2.2)octane adduct), DCC(dicyclohexyl carbodiimide), DCM (dichloromethane), dppf(1,1′-bis(diphenylphosphino)ferrocene), DIC (diisopropyl carbodiimide),DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO(dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (Ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MD Autoprep (Mass directed preparative HPLC), MeOH(methanol), MgSO₄ (magnesium sulfate), NMI (N-methyl imidazole), MS(mass spectrometry), MTBE (Methyl tert-butyl ether), Mtr. (4-Methoxy-2,3, 6-trimethylbenzensulfonyl), MW (microwave), NBS (N-bromosuccinimide), NaHCO₃ (sodium bicarbonate), NaBH₄ (sodium borohydride),NMM (N-methyl morpholine), NMR (Nuclear Magnetic Resonance), POA(phenoxyacetate), Py (pyridine), PyBOP®(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SFC(supercritical fluid chromatography), SPE (solid phase extraction), T3P(propylphosphonic anhydride), TBAF (tetra-n-butylammonium fluoride),TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet).

In general, the imidazo-oxadiazole and imidazo-thiadiazole compoundsaccording to Formula (I) and related formulae of this invention may beprepared from readily available starting materials. If such startingmaterials are not commercially available, they may be prepared bystandard synthetic techniques. In general, the synthesis pathways forany individual compound of Formula (I) and related formulae will dependon the specific substituents of each molecule, such factors beingappreciated by those of ordinary skill in the art. The following generalmethods and procedures described hereinafter in the examples may beemployed to prepare compounds of Formula (I) and related formulae.Reaction conditions depicted in the following schemes, such astemperatures, solvents, or co-reagents, are given as examples only andare not restrictive. It will be appreciated that where typical orpreferred experimental conditions (i.e. reaction temperatures, time,moles of reagents, solvents etc.) are given, other experimentalconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by the person skilled in the art,using routine optimisation procedures. For all the protection anddeprotection methods, see Philip J. Kocienski, in “Protecting Groups”,Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greeneand Peter G. M. Wuts in “Protective Groups in Organic Synthesis”, WileyInterscience, 3^(rd) Edition 1999.

Depending on the nature of R¹, R², R³, R⁴, R^(a), A, T, U, W and X,different synthetic strategies may be selected for the synthesis ofcompounds of Formula (I). In the process illustrated in the followingschemes R¹, R², R³, R⁴, R^(a), A, T, U, W and X, are as above-defined inthe description unless otherwise mentioned.

Compounds of Formula (Ia), wherein R¹, R², R³, R⁴, R^(a), A, U, W and Xare defined as above and T is —CONR⁵—, can be prepared from a carboxylicacid of Formula (II), wherein R¹, R^(a), U and X are defined as aboveand an amine (III), wherein R², R³, R⁴, R⁵, A and W are defined asabove, using coupling conditions well known to those skilled in the art.Alternatively, compounds of Formula (Ib), wherein R¹, R², R³, R⁴, R⁵,R^(a), A, U, W and X are defined as above and T is —NR⁵CO—, can beprepared from an amine of Formula (IV), wherein R¹, R^(a), U and X aredefined as above and a carboxylic acid (V), wherein R², R³, R⁴, A and Ware defined as above, using coupling conditions well known to thoseskilled in the art (Scheme 1).

Standard coupling agents, such as HATU, EDC, T3P or isobutylchloroformate can be used in the presence or not of a base such as DIEA,TEA or NMM in a suitable solvent such as DCM, DCE, THF or DMF at atemperature rising from about 0° C. to 100° C., for a time of 30 minutesto a few hours. Alternatively, carboxylic acid derivative (II) or (V)can be transformed into the corresponding acyl chloride and be coupledwith amine (III) or (IV) respectively, using conditions and methods wellknown to those skilled in the art, in the presence of a base such aspyridine, TEA or DIEA in a suitable solvent such as DCM, THF or DMF, ata temperature rising from about 0° C. to RT, preferably at RT, for a fewhours, affording compounds of Formula (Ia) and (Ib) respectively. On theother hand, carboxylic acid derivative (II) or (V) can be transformedinto the corresponding alkyl ester, such as methyl ester, and coupledwith amine derivatives (III) or (IV) respectively, in the presence ornot of AlMe₃ in DCE orbis(trimethylaluminum)-1,4-diazabicyclo(2.2.2)octane adduct in THF, at atemperature rising from about 0° C. to 100° C. for a few hours,affording compounds of Formula (Ia) and (Ib) respectively.

Alternatively, compounds of Formula (Ic), wherein R¹, R², R³, R⁴, R⁵,R^(a), A, U, W and X are defined as above and T is —NR⁵CONR⁵—, can beprepared from an amine of Formula (IV), wherein R¹, R^(a), U and X aredefined as above and an amine (III), wherein R², R³, R⁴, R⁵, A and W aredefined as above, using coupling conditions well known to those skilledin the art (Scheme 1). In a typical reaction conditions, but not limitedto it, amine (III) is reacted with CDI, followed by addition of amine(IV). Alternatively, isocyanate derived from amine (III) can becommercially available and directly used in the reaction with amine(IV).

Compounds of Formula (Id), wherein R¹, R², R³, R⁴, R^(a), A, U, W and Xare defined as above and T is —NR⁵—, can be prepared from intermediate(VI), wherein R¹, R^(a), U and X are defined as above and Hal is ahalogen such as I, Br, Cl or sulfonate ester, and an amine (III),wherein R², R³, R⁴, R⁵, R^(a), A and W are defined as above, via metalcatalyzed cross coupling reaction, such as Buchwald cross couplingreaction (Scheme 2). In a typical procedure, but not limited to it,intermediate (VI) and amine (III) are heated in a suitable solvent, suchas dioxane, in the presence of a base, such as Cs₂CO₃, and a catalyticamount of a palladium catalyst, such as Pd₂dba₃, with Xantphos asligand.

Compounds of Formula (Ie), wherein R¹, R², R³, R⁴, R^(a), A, U and X aredefined as above and T is —NR⁵—, W is a thiazole-containing bicycle andn=0-2, can be prepared from thiourea (VII), wherein R¹, R⁵, R^(a), U andX are defined as above, and α-halo ketone (VIII), wherein R², R³, R⁴, Aand n are defined as above (Scheme 3). Thiourea (VII) is prepared fromamine (IV), using condition well known by one skilled in the art, suchas but not limited to reaction with 1,1′-thiocarbonyldi-2-(1H)-pyridonefollowed by addition of methanolic ammonia. α-Halo ketone (VIII) can bereadily made by a number of methods known to one skilled in the art,such as but not limited to a three step process, nucleophilic additionto epoxide (IX), alcohol (X) oxidation followed by α-bromination of theresulting ketone (XI), affording α-bromoketone (VIII). Alternatively,α-bromoketone (VIII) can be transformed into 2-aminothiazole-containingbicycle (IIIa) that can be coupled with intermediate (VI), as previouslydepicted in Scheme 2.

Compounds of Formula (If), wherein R¹, R², R³, R⁴, R^(a), A, U and X aredefined as above and T is —NR⁵—, W is a triazole-containing bicycle andn=0-2, can be prepared as depicted in Scheme 4. Alkylation of thiourea(VII) with methyl iodide then provides the methyl isothioureas (VIII).The intermediates (VIII), wherein R¹, R⁵, R^(a), U and X are defined asabove, are coupled using standard methods, to functionalized carboxylicacids, such as acids (XII), wherein R², R³, R⁴, A and n are defined asabove, to afford the acylthioureas (XIII). Treatment of intermediate(XIII) with hydrazine provides triazole of formula (XIV). Triazole (XIV)undergo intramolecular alkylation using Hünig's base and sodium iodidein a solvent such as acetone or using and inorganic base, such aspotassium or cesium carbonate, and potassium iodide in DMF to afford thebicyclic triazole of formula (If).

Functionalized carboxylic acid (XII) required for the synthesis of thecompounds of formula (Ie) can be obtained using standard literaturemethods to those skilled in the art. In one variation, readily availablephenylacetic acid (XV) can be mono alkylated under basic conditions withchloroiodoalkanes to provide functionalized acid (XII) (Scheme 4).

Compounds of Formula (Ig) and (Ih), wherein R¹, R², R³, R⁴, R^(a), A, Uand X are defined as above, T is —NR⁵—, W is a substituted pyrimidineand n=0-2, can be prepared as depicted in Scheme 5. Amination of2,4-dichloropyrimidine with compounds of Formula (XVI), wherein R², R³,R⁴, R^(a), A and n are defined as above, yields intermediate (XVII) thatcan further react with amines of Formula (IV), either using S_(N)Arreaction conditions or metal catalyzed coupling conditions, yieldingcompounds of Formula (Ig). Alternatively, addition of amines of Formula(IV) to 2,4-dichloropyrimidine provides intermediates (XVIII) that canfurther react with an amine of Formula (XVI), yielding compounds ofFormula (Ih).

Compounds of Formula (Ii), wherein R¹, R², R³, R⁴, R^(a), A, W and X aredefined as above, U is an oxadiazole and T is —NR⁵—, can be prepared asdepicted in Scheme 6. Treatment of intermediate (XIX), wherein R¹, R andX are defined as above and ALK is a simple alkyl, such as methyl orethyl group, with hydrazine provide acyl hydrazone (XX). Addition ofisocyanate (XXI), wherein R², R³, R⁴, A and W are defined as above,yields intermediate (XXII) that undergoes cyclization in the presence ofbut not limited to PPh₃/CCl₄/NEt₃ or Tf₂O/NMI or TsCl/DMAP, attemperature ranging from 0° C. to 120° C.

Alternatively, compounds of Formula (Ii), wherein R¹, R², R³, R⁴, R^(a),A, W and X are defined as above, U is an oxadiazole and T is —NR⁵—, canbe prepared as depicted in Scheme 7. Cyclization of acyl hydrazone (XX)with CS2 yields [1,3,4]oxadiazole-2-thiols (XXIII). Addition of amine(III) provides compounds of Formula (Ii).

Imidazooxadiazole intermediate (XXVIIa), wherein R¹, R^(a) and U aredefined as above, X═O and Y is an halogen such as Cl, Br or I, —COOALKor a protected amino group, such as but not limited to —NHCOOCH₂Ph, canbe prepared following methods known to the one skill in the art. When Yis an halogen, such as Cl, Br or I, U is not a single bond. Typicalsynthetic pathways and conditions are depicted in Schemes 8 to 10 anddescribed hereinafter in the examples. One alternative is presented inScheme 8. Treatment of ester (XXIV), wherein U and Y are defined asabove, with hydrazine, provides acyl hydrazone (XXV) (Scheme 8). Thecoupling of the resulting acyl hydrazone (XXV) with N-protected aminoacid, such as but not limited to N-acetyl glycine, affords intermediate(XXVI). Intermediate (XXVI) undergoes cyclization in the presence of anexcess of POCl₃ in MeCN as solvent, affording intermediates (XXVIIa).

As alternative method, carboxylic acid of formula (XXVII), wherein U andY are defined as above, can be coupled with acyl hydrazone (XXVIII),using conditions well known to those skilled in the art, such as but notlimited to T3P, affording intermediate (XXIX). Intermediate (XXIX)undergoes cyclization with an excess of POCl₃ in MeCN as solvent,affording intermediates (XXVIIa).

On the other hand, treatment of N-protected amino ester (XXX), such asbut not limited to N-(tert-butoxycarbonyl)glycine methyl ester, withhydrazine provides acyl hydrazone (XXXI). Its coupling with carboxylicacid (XXVII), wherein U and Y are defined as above, affords intermediate(XXXII) that yields oxadiazole (XXXIII) upon treatment with Tf₂O/NMI orAPTS/TEA, at temperature ranging from 0° C. to 120° C. Aminedeprotection on (XXXIII), followed by coupling with a carboxylic acidsuch as R¹COOH gives intermediate (XXXIV). Final cyclization is achievedwith an excess of POCl₃ in MeCN as solvent, affording intermediates(XXVIIa), wherein R¹, R^(a) and U are defined as above, X═O and Y is anhalogen such as Cl, Br or I, —COOH, —COOAlk or a protected amino group,such as but not limited to —NHCOOCH₂Ph.

Alternatively, treatment of intermediate (XXXII) with Lawesson reagentyield formation of thiadiazole (XXXV). Amine deprotection on (XXXV),followed by coupling with a carboxylic acid such as R¹COOH givesintermediate (XXXVI). Final cyclization is achieved with an excess ofPOCl₃ in MeCN as solvent, affording intermediates (XXVIIb), wherein R¹,R^(a) and U are defined as above, X═S and Y is an halogen such as Cl, Bror I, —COOH, —COOAlk or a protected amino group, such as but not limitedto —NHCOOCH₂Ph.

The method for preparing amide derivatives of Formula (XXVIIa) selectedbelow:

-   2-(5-Bromo-pyridin-2-yl)-5-methyl-imidazo[5,1-b][1,2,4]oxadiazole,    hydrochloride salt-   3-methoxy-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine-   2-Methyl-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine-   4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine-   6-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-ylamine-   4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acid methyl    ester-   3-Methoxy-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic    acid methyl ester-   4-(5-Ethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acid methyl    ester-   4-(5,7-Dimethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acid    methyl ester-   2-(4-Bromo-phenyl)-5-methyl-imidazo[5,1-b][1,2,4]oxadiazole

is more particularly described in the examples.

The method for preparing amide derivatives of Formula (XXVIIb) selectedbelow:

-   5-Methylimidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acid ethyl    ester-   5-methylimidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acid-   3-Methoxy-4-(5-methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-phenylamine-   4-(5-Methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-benzoic acid    methyl ester-   4-(5-Methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-phenylamine

is more particularly described in the examples.

Compounds of Formulae (II) to (XXXVI) may be obtained either fromcommercial sources or they may be prepared from known compounds usingprocedures such as those described hereinafter in the examples, orconventional procedures, well known by one skilled in the art.

Compounds of Formulae (II) to (XXXVI), wherein R¹, R², R³, R⁴, R^(a), A,T, U, W, X and Y are defined as above, may be converted to alternativecompounds of Formulae (II) to (XXXVI), respectively, using suitableinterconversion procedures such as those described hereinafter in theexamples, or conventional interconversion procedures well known by oneskilled in the art.

If the above set of general synthetic methods is not applicable toobtain compounds according to Formula (I) and/or necessary intermediatesfor the synthesis of compounds of Formula (I), suitable methods ofpreparation known by a person skilled in the art should be used.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds offormula (I), which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compounds of formula (I), which contain an acid center, witha suitable base. Both types of salts may be formed or interconvertedusing ion-exchange resin techniques.

Depending on the conditions used, the reaction times are generallybetween a few minutes and 14 days, and the reaction temperature isbetween about −30° C. and 140° C., normally between −10° C. and 90° C.,in particular between about 0° C. and about 70° C.

Compounds of the formula (I) can furthermore be obtained by liberatingcompounds of the formula (I) from one of their functional derivatives bytreatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which conform to the formula (I), but contain correspondingprotected amino and/or hydroxyl groups instead of one or more free aminoand/or hydroxyl groups, preferably those which carry an amino-protectinggroup instead of an H atom bound to an N atom, in particular those whichcarry an R′—N group, in which R′ denotes an amino-protecting group,instead of an HN group, and/or those which carry a hydroxyl-protectinggroup instead of the H atom of a hydroxyl group, for example those whichconform to the formula (I), but carry a —COOR″ group, in which R″denotes a hydroxyl protecting group, instead of a —COOH group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size are furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxy-carbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-carbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC(tert-butoxy-carbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, suchas CBZ (“carbo-benz-oxy”), 4-methoxybenzyloxycarbonyl and FMOC; andaryl-sulfonyl, such as Mtr. Preferred amino-protecting groups are BOCand Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, 4-methoxybenzyl, p-nitro-benzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particu-larly preferred.

The term “solvates of the compounds” is taken to mean adductions ofinert solvent molecules onto the compounds which form owing to theirmutual attractive force. Solvates are, for example, mono- or dihydratesor alcoholates.

The compounds of the formula (I) are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as THF or dioxane,amides, such as DMF, halogenated hydrocarbons, such as DCM, furthermorealso alcohols, such as methanol, ethanol or isopropanol, and water.Mixtures of the above-mentioned solvents are furthermore suitable. TFAis preferably used in excess without addition of a further solvent, andperchloric acid is preferably used in the form of a mixture of aceticacid and 70% perchloric acid in the ratio 9:1. The reaction temperaturesfor the cleavage are advantageously between about 0 and about 50° C.,preferably between 15 and 30° C. (RT).

The BOC, OBut and Mtr groups can, for example, preferably be cleaved offusing TFA in DCM or using approximately 3 to 5N HCl in dioxane at 15-30°C., and the FMOC group can be cleaved off using an approximately 5 to50% solution of dimethylamine, diethylamine or piperidine in DMF at15-30° C.

Protecting groups which can be removed hydrogenolytically (for exampleCBZ, benzyl or the liberation of the amidino group from the oxadiazolederivative thereof) can be cleaved off, for example, by treatment withhydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those indicated above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 100° C. and pressures between about 1and 200 bar, preferably at 20-30° C. and 1-10 bar. Hydrogenolysis of theCBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol orusing ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at20-30° C.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,tri-fluoro-methylbenzene, chloroform or DCM; alcohols, such as methanol,ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers,such as diethyl ether, diisopropyl ether, tetrahydrofurane (THF) ordioxane; glycol ethers, such as ethylene glycol monomethyl or monoethylether or ethylene glycol dimethyl ether (diglyme); ketones, such asacetone or butanone; amides, such as acetamide, dimethylacetamide,N-methylpyrrolidone (NMP) or dimethyl-formamide (DMF); nitriles, such asacetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as EtOAc,or mixtures of the said solvents.

Esters can be saponified, for example, using LiOH, NaOH or KOH in water,water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0and 100° C. Furthermore, ester can be hydrolysed, for example, usingacetic acid, TFA or HCL.

Free amino groups can furthermore be acylated in a conventional mannerusing an acyl chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide or reacted with CH3-C(═NH)—OEt,advantageously in an inert solvent, such as DCM or THF and/or in thepresence of a base, such as triethylamine or pyridine, at temperaturesbetween −60° C. and +30° C.

Throughout the specification, the term leaving group preferably denotesCl, Br, I or a reactively modified OH group, such as, for example, anactivated ester, an imidazolide or alkylsulfonyloxy having 1-6 carbonatoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy). Radicals of this type for activation of thecarboxyl group in typical acylation reactions are described in theliterature (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart). Activated esters are advantageouslyformed in situ, for example through addition of HOBt orN-hydroxysuccinimide.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds of the formula I and so-calledprodrug compounds.

The term “prodrug derivatives” is taken to mean compounds of the formulaI which have been modified with, for example, alkyl or acyl groups,sugars like glucuronide or oligopeptides and which are rapidly cleavedin the organism to form the active compounds.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The formula (I) also encompasses the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates, salts and solvates of these compounds.

In a specific embodiment, when 2 chiral centers or more are present,compounds of Formula (I) are obtained as one diastereoisomer.

A “diastereoisomer” means that each of the chiral centers present in thecompound of Formula (I) is defined relatively to the others.

For all radicals and indices which occur more than once within the samechemical structure, their meanings are independent of one another.

The reactions are preferably carried out in an inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or DCM; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, THF (THF) or dioxane; glycol ethers, such as ethyleneglycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether(diglyme); ketones, such as acetone or butanone; amides, such asacetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, suchas acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as EtOAc,or mixtures of the said solvents.

Pharmaceutical Salts and Other Forms

The said compounds of the formula (I) can be used in their finalnon-salt form. On the other hand, the present invention also relates tothe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains an acidic center, such as a carboxyl group,one of its suitable salts can be formed by reacting the compound with asuitable base to give the corresponding base-addition salt. Such basesare, for example, alkali metal hydroxides, including potassium hydroxideand sodium hydroxide; alkaline earth metal hydroxides, such as magnesiumhydroxide and calcium hydroxide; and various organic bases, such aspiperidine, diethanolamine and N-methyl-glucamine (meglumine),benzathine, choline, diethanolamine, ethylenediamine, benethamine,diethylamine, piperazine, lysine, L-arginine, ammonia, triethanolamine,betaine, ethanolamine, morpholine and tromethamine. In the case ofcertain compounds of the formula I, which contain a basic center,acid-addition salts can be formed by treating these compounds withpharmaceutically acceptable organic and inorganic acids, for examplehydrogen halides, such as hydrogen chloride or hydrogen bromide, othermineral acids and corresponding salts thereof, such as sulfate, nitrateor phosphate and the like, and alkyl- and monoaryl-sulfonates, such asmethanesulfonate, ethanesulfonate, toluenesulfonate andbenzene-sulfonate, and other organic acids and corresponding saltsthereof, such as carbonate, acetate, trifluoro-acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate, ascorbate and thelike. Accordingly, pharmaceutically acceptable acid-addition salts ofthe compounds of the formula I include the following: acetate, adipate,alginate, aspartate, benzoate, benzene-sulfonate (besylate), bisulfate,bisulfite, bromide, camphorate, camphor-sulfonate, caprate, caprylate,chloride, chlorobenzoate, citrate, cyclamate, cinnamate, digluconate,dihydrogen-phosphate, dinitrobenzoate, dodecyl-sulfate, ethanesulfonate,formate, glycolate, fumarate, galacterate (from mucic acid),galacturonate, glucoheptanoate, gluco-nate, glutamate, glycerophosphate,hemi-succinate, hemisulfate, heptanoate, hexanoate, hippurate,hydro-chloride, hydrobromide, hydroiodide, 2-hydroxy-ethane-sulfonate,iodide, isethionate, isobutyrate, lactate, lactobionate, malate,maleate, malonate, mandelate, metaphosphate, methanesulfonate,methylbenzoate, mono-hydrogen-phosphate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, oleate, palmo-ate, pectinate, persulfate,phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate,but this does not represent a restriction. Both types of salts may beformed or interconverted preferably using ion-exchange resin techniques.

Furthermore, the base salts of the compounds of the formula I includealuminium, ammonium, calcium, copper, iron (III), iron(II), lithium,magnesium, manganese(III), manganese(II), potassium, sodium and zinksalts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzyl-ethylen-ediamine (benzathine),dicyclohexylamine, diethanol-amine, diethyl-amine,2-diethyl-amino-ethanol, 2-dimethyl-amino-ethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethyl-piperidine, glucamine,glucosamine, histidine, hydrabamine, isopropyl-amine, lido-caine,lysine, meglumine (N-methyl-D-glucamine), morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethanol-amine, triethylamine, trimethylamine, tripropyl-amine andtris(hydroxy-methyl)-methylamine (tromethamine), but this is notintended to represent a restriction.

Compounds of the formula I of the present invention which contain basicN2-containing groups can be quaternised using agents such as(C1-C4)-alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C1-C4)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C10-C18)alkyl halides,for example decyl, do-decyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl-(C1-C4)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compounds ofthe formula I can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tro-meth-amine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula (I) areprepared by bringing the free base form into contact with a sufficientamount of the desired acid, causing the formation of the salt in aconventional manner. The free base can be regenerated by bringing thesalt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts other-wise correspond tothe respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds of the formula I areprepared by bringing the free acid form into contact with a sufficientamount of the desired base, causing the formation of the salt in aconventional manner. The free acid can be regenerated by bringing thesalt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts other-wise correspond tothe respective free acid forms thereof.

If a compound of the formula (I) contains more than one group which iscapable of forming pharmaceutically acceptable salts of this type, theformula I also encompasses multiple salts. Typical multiple salt formsinclude, for example, bitartrate, diacetate, difumarate, dimeglumine,di-phosphate, disodium and trihydrochloride, but this is not intended torepresent a restriction.

With regard to that stated above, it can be seen that the term“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Owing to their molecular structure, the compounds of the formula (I) canbe chiral and can accordingly occur in various enantiomeric forms. Theycan therefore exist in racemic or in optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theIntermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the (R)and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, mandelic acid, malic acid, lactic acid, suitable N-protected aminoacids (for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

GENERAL METHODS

The compounds of invention have been named according to the standardsused in the program AutoNom (v1.0.1.1)

The compounds according to formula (I) can be prepared from readilyavailable starting materials by several synthetic approaches, using bothsolution-phase and solid-phase chemistry protocols or mixed solution andsolid phase protocols. Examples of synthetic pathways are describedbelow in the examples.

The commercially available starting materials used in the followingexperimental description were purchased from Aldrich, Sigma, ACROS orABCR unless otherwise reported.

¹H NMR analyses were carried out using BRUKER NMR, model DPX-300 MHzFT-NMR or Bruker Avance III 400 MHz. Residual signal of deuteratedsolvent was used as internal reference. Chemical shifts (δ) are reportedin ppm in relative to the residual solvent signal (δ=2.50 for ¹H NMR inDMSO-d₆, and 7.26 in CDCl₃). s (singlet), d (doublet), t (triplet), q(quadruplet), br (broad), quint (quintuplet).

The MS data provided in the examples described below were obtained usingeither: Method A: LC/MS Waters ZMD (ESI) or

Method B: a Micromass ZQ, single quadrapole LC/MS (ESCI)

HPLC analyses were obtained as followed:

Method A: Column:—Waters Xterra MS 5 μm C18, 100×4.6 mm. eluting withACN/10 mM ammonium bicarbonate (95% ACN after 4 min.) and a flow rate of2 mL/min.

Method B: Column:—Phenomenex Luna 5 μm C18 (2), 100×4.6 mm, eluting withACN/water/0.1% formic acid (100% ACN after 3.5 min.) and a flow rate of2 mL/min.

HPLC analyses were obtained as followed:

Method A: Column:—Waters Xterra MS 5 μm C18, 100×4.6 mm. eluting withACN/10 mM ammonium bicarbonate (95% ACN after 4 min.) and a flow rate of2 mL/min.

Method B: Column:—Phenomenex Luna 5 μm C18 (2), 100×4.6 mm, eluting withACN/water/0.1% formic acid (100% ACN after 3.5 min.) and a flow rate of2 mL/min. Detection of compounds was via a Micromass ZQ, singlequadrapole LC-MS instrument.

Method C: Column:—Phenomenex, Gemini NX, 3 μm C18, 150×4.6 mm. elutingwith ACN/10 mM ammonium bicarbonate (100% ACN after 9 min.) and a flowrate of 1 mL/min.

Method D: Column:—Supelco, Ascentis® Express C18 or Hichrom Halo C18,2.7 μm C18, 150×4.6 mm, eluting with ACN/water/0.1% formic acid (100%ACN after 9 min.) with a flow rate of 1 mL/min.

Method E: Column:—Hichrom ACE 3 C18-AR mixed mode column, 2.7 μm C18,100×4.6 mm, eluting with ACN/water/0.1% formic acid (100% ACN after 12min.) with a flow rate of 1 mL/min.

Method F: Column: Waters Xbridge™ C8, (50×4.6 mm), 3.5 μm; 8 mingradient H₂O:CH₃CN:TFA from 100:0:0.1% to 0:100:0.05% with a flow rateof 2.0 mL/min.

Analytical methods (A-F) are referred to in the protocols and tables ofdata outlined in the document below. UV detection (maxplot) for allmethods.

The mass directed preparative HPLC (MD Autoprep) purifications wereperformed with a mass directed autopurification Fractionlynx from Watersequipped with a Sunfire Prep C18 OBD column 19×100 mm 5 μm, unlessotherwise reported. All purifications were performed with a gradient ofACN/H₂O or ACN/H₂O/HCOOH (0.1%).

Preparative HPLC:

Alternatively, compounds were purified using reverse phase HPLC using aWaters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VISdetector, 2767 liquid handler). The Waters 2767 liquid handler acted asboth auto-sampler and fraction collector.

The column used for the preparative purification of the compounds was aWaters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenylat 10 um 19×150 mm.

Appropriate focused gradients were selected based on acetonitrile andmethanol solvent systems under either acidic or basic conditions. Thestandard gradient used was 5% ACN to 20% over 1 min, hold 1 min, to 80%ACN over 5 min, hold 4 min. Followed by 1 min 100% ACN and 1.5 minre-equilibration at initial conditions. A flow rate of 20 mL/min wasused.

The microwave chemistry was performed on a single mode microwave reactorEmrys™ Optimiser or Initiator™ Sixty from Biotage.

Intermediate 1:2-(5-Bromo-pyridin-2-yl)-5-methylimidazo[5,1-b][1,2,4]oxadiazole,Hydrochloride Salt

Step 1: 5-Bromo-pyridine-2-carboxylic acid hydrazide

5-Bromo-pyridine-2-carboxylic acid methyl ester (107 g, 495 mmol) wastaken in EtOH (2 L) at 25-26° C. under nitrogen atmosphere. Hydrazinehydrate (123 mL, 2475 mmol) was added to the reaction mixture andstirred for 48 h at 25° C. (reaction completion was confirmed by TLC).The reaction mixture was concentrated to get a crude product that wasprecipitated as a white solid (74.6 g, 70% yield). The crude product wastaken as such for the next step without further purification. ¹H NMR(300 MHz, DMSO-d₆) δ 9.99 (t, J=4.3 Hz, 1H), 8.74 (dd, J=2.4, 0.7 Hz,1H), 8.23 (dd, J=8.4, 2.4 Hz, 1H), 7.92 (dd, J=8.4, 0.7 Hz, 1H), 4.59(d, J=4.4 Hz, 2H). LC/MS (Method A): 218.0 (M+H)⁺.

Step 2:N-{2-[N′-(5-Bromo-pyridine-2-carbonyl)-hydrazino]-2-oxoethyl}-acetamide

Acetylamino-acetic acid (54.2 g, 463 mmol) was suspended in DMF (500 mL)and then di-imidazol-1-yl-methanone (82.6 g, 509 mmol) was added byportions. The mixture was reacted at room temperature until no more gasevolution was observed (1 h). A solution was obtained. It was addeddropwise over 20 min to a suspension of 5-bromo-pyridine-2-carboxylicacid hydrazide (50 g, 231 mmol) in DMF (500 mL). The reaction mixturewas stirred overnight at room temperature. Precipitation had occurredovernight and mixture was filtered off. The white solid was washed withMTBE (100 mL), dried under vacuum to finally obtain the pure expectedintermediate (27 g, 37% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (d,J=1.4 Hz, 1H), 10.19 (d, J=1.6 Hz, 1H), 8.93 (dd, J=2.3, 0.7 Hz, 1H),8.40 (dd, J=8.4, 2.3 Hz, 1H), 8.32 (t, J=5.8 Hz, 1H), 8.07 (dd, J=8.4,0.7 Hz, 1H), 3.93 (d, J=5.8 Hz, 2H), 1.98 (s, 3H). LC/MS (Method A):317.2 (M+H)⁺.

Step 3:2-(5-Bromo-pyridin-2-yl)-5-methylimidazo[5,1-b][1,2,4]oxadiazole,Hydrochloride Salt

N-{2-[N′-(5-Bromo-pyridine-2-carbonyl)-hydrazino]-2-oxo-ethyl}-acetamide(26 g, 86 mmol) was added in portions to Eaton's reagent (260 mL).Resulting viscous mixture was heated to 110° C. for 7 h after what LC/MSindicated a ˜1:2 mixture of oxadiazole:imidazooxadiazole. The reactionwas allowed to cool to 25° C. and was added drop-wise to a solution ofK₂CO₃ 50% (800 mL). Strong gas evolution occurred upon addition. Thethick mixture was diluted with water (800 mL) and was extracted with DCM(2×800 mL). Organic layers were combined, dried over MgSO₄, filtered andevaporated to dryness to obtain a mixture of the titled compound and itsopen form as a brown solid (16.2 g). This brown solid was taken in MeCN(320 mL). POCl₃ (5.07 mL, 55 mmol) was added drop-wise and mixture washeated to ET=90° C. The cyclization was completed within 3.5 h accordingto LC/MS. Reaction mixture was cooled to RT and acetonitrile (˜200 mL)was evaporated. Resulting suspension was filtered. Solid was washed withEtOAc (25 mL) and then dried overnight under vacuum. Finally a purplesolid was isolated as the hydrochloride salt of the expected compound(12.5 g, 46% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (dd, J=2.4, 0.7Hz, 1H), 8.51 (dd, J=8.5, 2.3 Hz, 1H), 8.29 (dd, J=8.4, 0.8 Hz, 1H),7.54 (s, 1H), 2.81 (s, 3H). LC/MS (Method A): 281.1 (M+H)⁺.

Intermediate 2:3-methoxy-4-(5-methylimidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine

Step 1: 2-methoxy-4-nitrobenzohydrazide

To a suspension of 2-methoxy-4-nitrobenzoic acid (10 g, 50.7 mmol) inchloroform (50 mL) under nitrogen was added thionyl chloride (12 mL, 162mmol) slowly, followed by DMF (four drops). After 16 hours at 25° C.,the reaction mixture was concentrated under reduced pressure. Theresidue was cooled to 0° C. and diluted slowly with MeOH (50 mL),followed by hydrazine hydrate (35% aqueous solution, 13.6 mL, 152 mmol).The reaction mixture was sealed and stirred for 6 hours at 25° C. Theresulting precipitate was collected by filtration, washed with water,and then dried under vacuum to afford a yellow solid as a mixture of thetitle compound and the methyl ester. To this solid was added MeOH (50mL), followed by hydrazine hydrate (35% aqueous solution, 13.6 mL, 152mmol). After 24 hours at 80° C. the resulting precipitate was collectedby filtration, washed with water, and then dried under vacuum to affordthe title compound (7.3 g, 69% yield). LC/MS (Method B): 212 (M+H)⁺.

Step 2:N-(2-(2-(2-methoxy-4-nitrobenzoyl)hydrazinyl)-2-oxoethyl)acetamide

To a suspension of N-acetylglycine (6.9 g, 59.8 mmol) in DMF (30 mL) wasadded CDI (10.1 g, 62.4 mmol) portionwise over 20 minutes. After 30minutes a solution of 2-methoxy-4-nitrobenzohydrazide (6.3 g, 29.6 mmol)in DMF (50 mL) was added. After 16 hours at 25° C. the reaction wasconcentrated under reduced pressure. The residue was diluted in 2Maqueous HCl to give a precipitate, which was collected by filtration,washed with water and then dried under vacuum to afford the titlecompound (2.6 g, 28% yield). LC/MS (Method B): 311 (M+H)⁺.

Step 3:2-(2-methoxy-4-nitrophenyl)-5-methylimidazo[5,1-b][1,2,4]oxadiazole

To a suspension ofN-(2-(2-(2-methoxy-4-nitrobenzoyl)hydrazinyl)-2-oxoethyl)acetamide (2.9g, 9.35 mmol) in MeCN (50 mL), was added phosphoryl chloride (8.7 mL,93.5 mmol). After 6 hours at 90° C. the reaction was cooled to 25° C.and then concentrated under reduced pressure. The residue was quenchedwith ice-water, basified using saturated aqueous Na₂CO₃ solution andthen extracted using EtOAc. The organic layers were combined, washedwith water and brine, dried (MgSO₄) and concentrated under reducedpressure to afford the title compound (2.3 g, 90% yield). ¹H NMR (400MHz, CHCl₃-d): δ 7.99-7.92 (m, 3H); 6.49 (s, 1H); 4.13 (s, 3H); 2.60 (s,3H). LC/MS (Method B): 275 (M+H)⁺.

Step 4:3-methoxy-4-(5-methylimidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine

A slurry was prepared of2-(2-methoxy-4-nitrophenyl)-5-methylimidazo[5,1-b][1,2,4]oxadiazole (2.3g, 8.4 mmol), iron powder (2.2 g, 42 mmol) and ammonium chloride (670mg, 12.6 mmol) in THF (10 mL)/EtOH (10 mL)/water (3 mL). This reactionwas sealed under nitrogen and rapidly heated to 90° C. for 1 hour. Thereaction was then filtered through a celite pad, washed with MeOH (100mL) and concentrated in vacuo. The crude product was dissolved in EtOAc,washed with dilute aqueous NaHCO₃ solution and filtered. The organicphase was then washed with water, brine and dried (MgSO₄) andconcentrated under reduced pressure to give a pale yellow powder (1.4 g,68% yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 6.39 (s, 1H); 6.34 (d, J=1.95Hz, 1H); 6.29 (dd, J=8.57, 1.94 Hz, 1H); 6.14 (s, 2H); 3.83 (s, 3H);2.40 (s, 3H).

Intermediate 3:2-Methyl-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine

Step 1: 3-methyl-4-nitrobenzohydrazide

To a suspension of methyl 3-methyl-4-nitrobenzoate (10 g, 51 mmol) inEtOH (100 mL), was added hydrazine hydrate (55% aqueous solution, 8.50mL, 150 mmol) in one portion. After 48 hours at 90° C. the reaction wascooled to 0° C. The reaction mixture was diluted with water (50 mL) andstirred for a further 5 minutes. The resulting precipitate was collectedby filtration, washed with water, and then dried under vacuum to affordthe title compound as a white solid (7.78 g, 78% yield). 1H NMR (400MHz, DMSO-d⁶): δ 10.02 (s, 1H); 8.04 (d, J=8.45 Hz, 1H); 7.92 (s, 1H);7.83 (dd, J=8.44, 1.94 Hz, 1H); 4.60 (s, 2H); 2.54 (s, 3H). LC/MS(Method B): 196 (M+H)⁺.

Step 2:N-(2-(2-(3-methyl-4-nitrobenzoyl)hydrazinyl)-2-oxoethyl)acetamide

To a suspension of 3-methyl-4-nitrobenzohydrazide (7.78 g, 40 mmol) inDCM (100 mL) under nitrogen was added EDC-HCl (8.5 g, 44 mmol), followedby triethylamine (18.76 mL, 140 mmol). After 15 minutes N-acetylglycine(5.2 g, 44 mmol) was added and the reaction was stirred for a further 16hours. The reaction mixture was diluted with DCM and water, and thenbasified with 1M aqueous NaOH and extracted using DCM. The aqueous phasewas then acidified with concentrated aqueous HCl. The resultingprecipitate was collected by filtration, washed with water, followed byEt₂O and then dried under vacuum to afford the title compound as ayellow solid (4.95 g, 42% yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 10.61 (s,1H); 10.09 (s, 1H); 8.22 (t, J=5.95 Hz, 1H); 8.18-8.03 (m, 1H); 7.96 (s,1H); 7.93-7.85 (m, 1H); 3.82 (d, J=5.93 Hz, 2H); 2.51 (s, 3H); 1.88 (s,3H). LC/MS (Method B): 295 (M+H)⁺.

Step 3:5-methyl-2-(3-methyl-4-nitrophenyl)imidazo[5,1-b][1,2,4]oxadiazole

To a suspension ofN-(2-(2-(3-methyl-4-nitrobenzoyl)hydrazinyl)-2-oxoethyl)acetamide (0.95g, 3.2 mmol) in MeCN (12 mL), was added phosphoryl chloride (1.5 mL,16.1 mmol) dropwise. After 2 hours at 110° C., the reaction was cooledto 25° C. then concentrated under reduced pressure. The residue wasquenched with ice-water, basified using saturated aqueous Na₂CO₃solution and then extracted using DCM. The organic layers were combined,washed with water and brine, dried (MgSO₄) and concentrated underreduced pressure. The resulting crude residue was purified bychromatography (silica gel, DCM/MeOH) and the resultant solid wastriturated with Et₂O to afford the title compound as a yellow solid(0.72 g, 86% yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 8.18 (t, J=3.94 Hz,2H); 8.08 (dd, J=8.54, 1.91 Hz, 1H); 6.57 (s, 1H); 2.61 (s, 3H); 2.47(s, 3H). LC/MS (Method B): 259 (M+H)⁺.

Step 4:2-Methyl-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine

To a suspension of5-methyl-2-(3-methyl-4-nitrophenyl)imidazo[5,1-b][1,2,4]oxadiazole (1.90g, 7.4 mmol) in acetic acid (19 mL) and EtOH (19 mL) was added ironpowder (325 mesh, 1.62 g, 29.4 mmol) portionwise (exotherm). After 3hours the reaction had cooled to 25° C. and was filtered over celite andconcentrated under reduced pressure. The residue was diluted with EtOAcand water, basified with saturated aqueous Na₂CO₃ solution and thenextracted using EtOAc. The organic layers were combined, washed withwater and brine, dried (MgSO₄) and concentrated under reduced pressure.The resulting crude residue was triturated with Et₂O to afford the titlecompound as a yellow solid (1.4 g, 83% yield). ¹H NMR (400 MHz,DMSO-d⁶): δ 7.61-7.54 (m, 2H); 6.73 (d, J=8.36 Hz, 1H); 6.42 (s, 1H);5.89 (s, 2H); 2.40 (s, 3H); 2.13 (s, 3H). LC/MS (Method B): 229 (M+H)⁺.

Intermediate 4;4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine

Step 1: N-(2-(2-(4-nitrobenzoyl)hydrazinyl)-2-oxoethyl)acetamide

To N-acetylglycine (3.46 g, 20 mmol), 4-nitrophenylhydrazine (3.6 g, 20mmol) and EDC-HCl (7.6 g, 40 mmol) in THF (40 mL) was addedtriethylamine (5.5 mL, 40 mmol). After 60 hours at 25° C., the reactionmixture was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate and aqueous sodium carbonate solution.The aqueous solution was acidified and the precipitate obtained wascollected by filtration, washed with water and dried at 50° C. to affordthe title compound as an orange powder (4.4 g, 78% yield). ¹H NMR (400MHz, DMSO-d d⁶): δ 10.71 (s, 1H); 10.11 (s, 1H); 8.39-8.33 (m, 2H); 8.23(t, J=5.94 Hz, 1H); 8.13-8.06 (m, 2H); 3.83 (d, J=5.92 Hz, 2H);1.96-1.78 (m, 3H). LC/MS (Method B): 281.0 (M+H)⁺.

Step 2: 5-methyl-2-(4-nitrophenyl)imidazo[5,1-b][1,2,4]oxadiazole

N-(2-(2-(4-nitrobenzoyl)hydrazinyl)-2-oxoethyl)acetamide (4.45 g, 15.8mmol) and phosphorus oxychloride (20 mL) in acetonitrile (40 mL) wereheated at reflux for 3 hours. The reaction mixture was concentratedunder vacuum and the residue was treated with ice, basified with aqueoussodium hydroxide and extracted with dichloromethane. The organic layerswere combined, dried (MgSO₄) and concentrated under reduced pressure toafford the title compound as an orange solid (2.7 g, 69% yield). ¹H NMR(400 MHz, DMSO-d□): δ 8.49-8.42 (m, 2H); 8.35-8.30 (m, 2H); 6.89 (s,1H); 2.57 (s, 3H). LC/MS (Method B): 245.0 (M−H)−.

Step 3: 4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenylamine

5-methyl-2-(4-nitrophenyl)imidazo[5,1-b][1,2,4]oxadiazole (500 mg, 2.05mmol) and iron powder (1.14 g, 20.5 mmol) in acetic acid (10 mL) werestirred at 25° C. for 18 hours. The reaction mixture was filtered andwashed with acetic acid. The filtrate was concentrated under reducedpressure, basified with aqueous sodium carbonate solution and extractedwith chloroform. The organic layers were combined, dried (MgSO₄) andconcentrated under reduced pressure to afford the title compound as ayellow solid (200 mg, 45% yield). ¹H NMR 6 (400 MHz, DMSO-d⁶): 7.68 (2H,d, J=8.52 Hz), 6.68 (2H, d, J=8.55 Hz), 6.46-6.39 (1H, s), 6.16 (2H, s),2.40 (3H, s). LC/MS (Method B): 215.0 (M+H)⁺.

Intermediate 5:6-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-ylamine

Step 1: 5-Nitro-pyridine-2-carboxylic acid hydrazide

5-Nitro-pyridine-2-carboxylic acid methyl ester (104 g, 571 mmol) wastaken in EtOH (1.0 L) at 25-26° C. under nitrogen atmosphere. Hydrazinehydrate (141 mL, 2853 mmol) was added to the reaction mixture that wasstirred at 25° C. for 48 h (reaction completion was confirmed by LC/MS).An orange suspension was obtained. After filtration and drying undervacuum an orange solid was isolated as the expected title compound (110g, 100% yield). The crude product was taken as such for the next stepwithout further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 10.28 (s, 1H),9.34 (dd, J=2.6, 0.7 Hz, 1H), 8.74 (dd, J=8.6, 2.6 Hz, 1H), 8.22 (dd,J=8.6, 0.7 Hz, 1H), 4.76 (s, 2H). LC/MS (Method A): 183.2 (M+H)⁺.

Step 2:N-{2-[N′-(5-Nitro-pyridine-2-carbonyl)-hydrazino]-2-oxoethyl}-acetamide

N-Acetyl glycine (90 g, 768.6 mmol) was suspended in DMF (0.7 L) at25-26° C. under vigorous stirring. Carbonyl Di-imidazole (137.1 g, 845mmol) was added by portions to the reaction mixture. The resultingreaction was stirred at 25° C. for 0.5 h and added over a period of 30minutes to a suspension of 5-nitro-pyridine-2-carboxylic acid hydrazide(70 g, 384 mmol) in DMF (0.7 L). The reaction was stirred for 3 hours atroom temperature (reaction completion was confirmed by LC/MS). Theexpected compound was precipitated by addition of toluene (2.1 L, 30vol). The resulting suspension was stirred at 25° C. overnight and theprecipitate collected by filtration and washed with EtOAc (25 mL). Thecrude product was suspended in MeOH (2 L) overnight at 70° C. untilobtaining a fine suspension and precipitated as a white solid (77 g, 71%yield). ¹H NMR (300 MHz, DMSO) δ 10.82 (s, 1H), 10.17 (s, 1H), 9.40 (dd,J=2.7, 0.7 Hz, 1H), 8.78 (dd, J=8.6, 2.6 Hz, 1H), 8.36-8.11 (m, 2H),3.83 (d, J=5.9 Hz, 2H), 1.87 (s, 3H). LC/MS (Method A): 282.3 (M+H)⁺.

Step 3:5-Methyl-2-(5-nitro-pyridin-2-yl)-imidazo[5,1-b][1,2,4]oxadiazole

N-{2-[N′-(5-Nitro-pyridine-2-carbonyl)-hydrazino]-2-oxo-ethyl}-acetamide(20 g, 71 mmol) was added in portions to Eaton's reagent (150 mL).Resulting viscous mixture was heated to 110° C. for 8 h after what LC/MSindicated a ˜1:2 mixture of oxadiazole:imidazooxadiazole. The reactionwas allowed to cool to 25° C. and was added drop-wise to a solution ofK₂CO₃ 50% (800 mL). Strong gas evolution occurred upon addition. Thethick mixture was diluted with water (2.0 L) and was extracted with DCM(3×700 mL). Organic layers were combined, dried over MgSO₄, filtered andevaporated to dryness to obtain a mixture of the title compound and itsopen form as a yellow solid (10.3 g). This material was taken in MeCN(200 mL). POCl₃ (3.75 mL, 41 mmol) was added drop-wise and mixture washeated to ET=90° C. The cyclization was completed within 3 h 30according to LC/MS. Reaction mixture was cooled to RT and MeCN (˜150 mL)was evaporated. Resulting suspension was quenched by addition of 20% aq.K₂CO₃ sol. (100 mL). Strong foaming occurred during addition. Theaqueous mixture was extracted with DCM (3×100 mL). Organic layers werecombined and evaporated to dryness to obtain a brown solid which wassuspended in a mixture of EtOAc/toluene (20 mL/20 mL). The suspensionwas filtered and dried overnight under vacuum to finally obtain thetitle compound as a brown solid (7.3 g, 42% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 9.62 (dd, J=2.6, 0.7 Hz, 1H), 8.89 (dd, J=8.7, 2.6 Hz, 1H),8.53 (dd, J=8.7, 0.7 Hz, 1H), 7.46 (s, 1H), 2.76 (s, 3H). LC/MS (MethodA): 246.1 (M+H)⁺.

Step 4:6-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-ylamine

A suspension of5-methyl-2-(5-nitro-pyridin-2-yl)-imidazo[5,1-b][1,2,4]oxadiazole (5.2g, 21.2 mmol) in 30% AcOH (100 mL) was degassed under nitrogenatmosphere at 25° C. 10% Palladium on activated charcoal (750 mg, 0.35mmol) was added and the reaction hydrogenated (P=20 bars) at 25° C. for18 hours (reaction completion was confirmed by LC/MS). The suspensionwas filtered over a celite pad and rinsed with 30% aq acetic acid (10mL). The filtrate was evaporated to dryness, stripped with toluene(3×100 mL) and then dried under vacuum to afford a beige solid. Thecrude was suspended in MeCN (50 mL), filtered and dried to finallyobtain the expected product as a beige solid (3.41 g, 75% yield). ¹H NMR(DMSO-d₆, 300 MHz) δ 8.07 (dd, J=0.7, 2.7 Hz, 1H), 7.82 (dd, J=0.7, 8.6Hz, 1H), 7.03 (dd, J=2.7, 8.6 Hz, 1H), 6.46 (s, 1H), 6.35 (s, 2H), 2.42(s, 3H). LC/MS (Method A): 216.0 (M+H)⁺.

Intermediate 6: 4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoicacid methyl ester

Step 1: Dimethyl Terephthalate

Terephthalic acid (20 g, 120 mmol) was taken in MeOH (200 mL) at 25-26°C. under nitrogen atmosphere. Thionyl chloride (42.9 g, 361 mmol) wasadded slowly over 10 minutes. The reaction mixture was heated to 80° C.for 12 h (reaction completion was confirmed by LCMS). The reactionmixture was cooled to 25-26° C. and concentrated to get the crudeproduct as white solid (25 g). The crude product was taken up in 10%NaHCO₃ solution (50 mL) and stirred for 10 minutes. The precipitatedsolids were filtered, washed with water (50 mL) and dried to get thepure product as white solid (19 g, 82% yield). ¹H NMR (DMSO-d₆, 400 MHz)δ 8.06 (s, 2H), 3.87 (s, 3H). HPLC (Method F) Rt 3.68 min (Purity:99.5%).

Step 2: 4-Hydrazinocarbonyl-Benzoic Acid Methyl Ester

Dimethyl terephthalate (19 g, 97 mmol) was taken in EtOH (200 mL) at25-26° C. under nitrogen atmosphere. Hydrazine hydrate (5.39 g, 0.107mol) was added to the reaction mixture and stirred for 12 h at 90° C.(reaction completion was confirmed by TLC). The reaction mixture wascooled to 25-26° C. and concentrated to get crude product as white solid(20 g, 100% yield) The crude product was taken as such for the next stepwithout further purification. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.96 (s, 1H),8.01-7.99 (m, 2H), 7.93-7.91 (m, 2H), 4.58 (b, 2H), 3.86 (s, 3H). LC/MS(Method A): 195.3 (M+H)⁺. HPLC (Method F) Rt 0.354 min (Purity: 70.3%).

Step 3: 4-[N′-(2-Acetylamino-acetyl)-hydrazinocarbonyl]-benzoic acidmethyl ester

4-Hydrazinocarbonyl-benzoic acid methyl ester (10 g, 51 mmol) was takenin DCM (100 mL) at 25-26° C. under nitrogen atmosphere. EDC-HCl (8.98 g,56 mmol), HOBT (7.6 g, 56 mmol) and triethylamine (26.0 g, 257 mmol)were added and stirred for 15 minutes. N-acetyl glycine (6.63 g, 56mmol) was added to the reaction mixture and stirred for 12 h (reactioncompletion was confirmed by TLC). The reaction mixture was quenched withice water (50 mL) and stirred for 15 minutes. The precipitated solidswere filtered and dried to get the crude product as light brown solid(12 g, 95% yield). The crude product was directly taken for next stepwithout further purification.

Step 4: 4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acidmethyl ester

4-[N′-(2-Acetylamino-acetyl)-hydrazinocarbonyl]-benzoic acid methylester (12.0 g, 40 mmol) was dissolved in CH₃CN (120 mL) at 25-26° C.under nitrogen atmosphere. POCl₃ (60 mL) was added slowly over 10minutes and the reaction mixture heated at 110° C. for 12 h (reactioncompletion was confirmed by TLC). The reaction mixture was cooled to25-26° C. and concentrated to get a brown liquid residue (20 g). Theresidue was quenched with ice water (50 mL) and basified with solidK₂CO₃ and desired compound extracted with CH₂Cl₂ (100 mL×2). The CH₂Cl₂layer was washed with water (100 mL), brine solution (50 mL), dried overNa₂SO₄ and concentrated to get the crude product as brown solid. Thecrude product was purified by column chromatography (60-120 mesh silicagel; eluent: 40% EtOAc in pet ether) to get the product as yellow solid(3.1 g, 30% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.15 (s, 4H), 6.53 (s,1H), 3.89 (s, 3H), 2.44 (s, 3H). LC/MS (Method A): 258.0 (M+H)⁺. HPLC(Method F) Rt 2.35 min (Purity: 97.2%).

Intermediate 7:3-Methoxy-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acidmethyl ester

Step 1: 4-Bromo-2-methoxy-benzoic acid hydrazide

4-Bromo-2-methoxybenzoic acid (30 g, 122.4 mmol) was taken in MeOH (300mL). To this solution, hydrazine hydrate (20.6 mL, 428 mmol) was addedand heated 3 h at 60° C. The reaction mixture was cooled to RT andsolvents removed under reduced pressure. The crude reaction mixture wasquenched with water, stirred for 10 min and filtered off to afford thetitle compound as an off white solid (28 g, 94% yield). ¹H NMR (DMSO-d₆,400 MHz): δ 9.22 (bs, 1H), 7.57-7.55 (d, J=8.2 Hz, 1H), 7.30-7.30 (d,J=1.7 Hz, 1H), 7.22-7.19 (m, 1H), 4.52-4.51 (d, 2H), 3.86 (s, 3H).

Step 2:N-{2-[N′-(4-Bromo-2-methoxy-benzoyl)-hydrazino]-2-oxo-ethyl}-acetamide

4-Bromo-2-methoxy-benzoic acid hydrazide (28 g, 114.2 mmol), N-acetylglycine (13.3 g, 114.2 mmol) and triethylamine (31.6 mL, 284 mmol) wereintroduced in a THF solution (300 mL) at 0° C. To this ice cooledsolution, T3P (79.8 g, 50% in EtOAc, 125.6 mmol) was added in drops andthe reaction mixture heated at 80° C. for 12 h. Upon completion, thereaction mixture was cooled down to room temperature and the solventremoved under vacuum. The crude material was quenched with ice andneutralized with sodium bicarbonate solution. The resulting mixture wasstirred for 20 minutes and filtered to afford the title compound as anoff white solid (32 g, 82% yield). ¹H NMR (DMSO-d₆, 400 MHz): δ 10.18(bs, 1H), 9.91 (bs, 1H), 8.17-8.14 (t, J=5.8 Hz, 1H), 7.59-7.57 (d,J=8.2 Hz, 1H), 7.36-7.35 (d, J=1.7 Hz, 1H), 7.26-7.24 (m, 1H), 3.88 (s,3H), 3.79-3.77 (d, 2H), 1.85 (s, 3H).

Step 3:2-(4-Bromo-2-methoxy-phenyl)-5-methyl-imidazo[5,1-b][1,2,4]oxadiazole

A suspension ofN-{2-[N′-(4-bromo-2-methoxy-benzoyl)-hydrazino]-2-oxo-ethyl}-acetamide(21 g, 612 mmol) and phosphorous oxychloride (27.9 mL, 306 mmol) washeated 12 hours at 80° C. in MeCN (200 mL). When the reaction wasfinished, it was cooled to RT and the organic solvent removed undervacuum. The residual liquid was quenched with ice and neutralized with asaturated potassium carbonate solution to pH 9 and filtered to affordthe title compound as pale brown solid (16 g, 85.1% yield). ¹H NMR(DMSO-d₆, 400 MHz): δ 7.82-7.80 (d, J=8.3 Hz, 1H), 7.53-7.52 (d, J=1.7Hz, 1H), 7.37-7.35 (m, 1H) 6.48 (s, 1H), 3.95 (s, 3H) 2.42 (s, 3H).

Step 4:3-Methoxy-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acidmethyl ester

To a solution of2-(4-bromo-2-methoxy-phenyl)-5-methyl-imidazo[5,1-b][1,2,4]oxadiazole(13 g, 0.042 mol) in MeOH (130 mL) was added triethylamine (14.6 mL,0.1055 mol) and degassed with carbon monoxide. To this degassed mixture1,1-Bis diphenyl phosphine ferrocene palladium (II) chloride 1:1 complexwith DCM (3.44 g, 4.22 mmol) was added and heated to 60° C. for 18 h.The mixture was cooled to RT and passed through a celite bed to removethe catalyst. The solvent was removed under reduced pressure. Crudematerial was purified by trituration in MeOH (35 mL). The solvent wasremoved by filtration and product was dried under suction to afford thetitle compound as an off white solid (5.3 g, 43.72% yield). ¹H NMR(DMSO-d₆, 400 MHz): δ 8.06-8.04 (t, J=0.9 Hz, 1H), 7.72-7.69 (t, J=7.5Hz, 2H) 6.50 (s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 2.50-2.48 (s, 3H).LC/MS (Method A): 288 (M+H)⁺. HPLC (Method F) Rt 2.4 min (Purity:98.7%).

Intermediate 8: 4-(5-Ethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoicacid methyl ester

Step 1: 4-Bromobenzoic Acid Methyl Ester

To an ice cold solution of 4-bromo benzoic acid (50 g, 248.0 mmol) in adry mixture of DCM and MeOH (1:1, 500 mL), was added thionyl chloride(55 mL, 746.0 mmol) in drops. The reaction mixture was stirred at 0° C.for 30 min and then heated to 60° C. for 5 h. After cooling the reactionmixture to RT, the solvent was removed under reduced pressure. Theresidue was quenched with ice and neutralised with solid sodiumbicarbonate. The product was extracted with EtOAc (3×250 mL). Thecombined organic layers were washed with water, brine solution and driedover sodium sulphate. The solvent was removed under vacuum to afford thetitle compound as an off white solid (45 g, 84% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 7.88-7.88 (dd, J=2.0, 2.0 Hz, 2H), 7.75-7.72 (m, 2H), 3.84(s, 3H).

Step 2: 4-Bromo-Benzoic Acid Hydrazide

To a stirred solution of methyl 4-bromobenzoic acid methyl ester (45 g,209.0 mmol) in MeOH (500 mL), hydrazine hydrate (39.31 g, 627.0 mmol)was added at RT and heated to 65° C. for 12 h. After cooling thereaction mixture to RT, the solvent was removed under reduced pressure.The residue was slurred with diethyl ether (300 mL). The solid wasfiltered off and dried under suction to afford the title compound as anoff white solid (40 g, 93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s,1H), 7.76-7.73 (m, 2H), 7.66-7.64 (m, 2H), 4.49 (s, 2H).

Step 3: Propionylamino-Acetic Acid Tert-Butyl Ester

To an ice cold suspension of glycine tert-butyl ester hydrochloride (50g, 298.0 mmol) in dry MeCN (500 mL) was added potassium carbonate (82.33g, 596.6 mmol) in portions. The mixture was stirred at the sametemperature for 30 min. To this mixture, propionyl chloride (41.55 g,449.0 mmol) was added in drops and continued stirring at the sametemperature for 30 min. The reaction mixture was heated to 65° C. for 12h and then cooled to RT to be filtered off. The filtrate was removedunder reduced pressure to afford the title compound as a colorlessliquid (25 g). The crude product was taken as such for the next stepwithout purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09-8.06 (t, J=5.6Hz, 1H), 3.69-3.66 (t, 2H), 2.14-2.06 (m, 2H), 1.3 (s, 9H) 1.0-0.96 (t,3H).

Step 4: Propionylamino-Acetic Acid

To a stirred solution of propionylamino-acetic acid tert-butyl ester (25g, 133.0 mmol) in DCM (250 mL) was added HCl in dioxane (3M, 100 mL). Itwas stirred at 25° C. for 12 h. When the reaction was completed, thesolvent was removed under reduced pressure to afford the title compoundas an off white solid (21 g, 94% yield). The solid was carried out fornext step without any purification. ¹H NMR (400 MHz, DMSO-d₆) δ8.20-8.19 (t, J=4.8 Hz, 1H), 8.08-8.06 (d, J=5.1 Hz) 3.80-3.76 (m, 2H),2.14-2.08 (m, 2H), 1.21-1.15 (t, 3H).

Step 5: N-{2-[N′-(4-Bromo-benzoyl)-hydrazino]-2-oxo-ethyl}-propionamide

A mixture of 4-bromo-benzoic acid hydrazide (12.8 g, 59.0 mmol),propionylamino-acetic acid (10 g, 59.0 mmol) and triethylamine (20.8 mL,149.0 mmol) in THF (150 mL) was cooled at 0° C. To this reactionmixture, T3P (41.8 mL, 50% w/w in EtOAc, 432.0 mmol) was added drop-wiseand heated to 70° C. for 12 h. When the reaction was completed, thereaction mixture was cooled to RT. The solvent was removed under vacuum.The residue was quenched with ice and neutralized with solid sodiumbicarbonate and extracted with EtOAc (3×100 mL). The combined organiclayers were washed with water, brine solution and dried over sodiumsulphate. The solvent was removed under vacuum. The residue was purifiedby stirring with Et₂O (50 mL), filtered and dried under suction toafford the title compound as an off white solid (6 g, 30% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.97 (s, 1H), 8.12-8.09 (t, J=5.9Hz, 1H), 7.76-7.73 (m, 2H), 7.66-7.64 (m, 2H), 3.80-3.78 (d, 2H),2.17-2.11 (t, 2H), 1.01-0.97 (t, 3H).

Step 6: 2-(4-Bromo-phenyl)-5-ethyl-imidazo[5,1-b][1,2,4]oxadiazole

To a suspension ofN-{2-[N′-(4-Bromo-benzoyl)-hydrazino]-2-oxo-ethyl}-propionamide (10 g,30.0 mmol) in MeCN (250 mL), phosphorous oxychloride (14.7 mL, 152.0mmol) was added in drops at RT. This mixture was heated to 90° C. for 12h. After cooling, the reaction mixture was allowed to RT and the solventremoved under reduced pressure. The residue was quenched with ice,neutralized with solid potassium carbonate and the expected compoundextracted with EtOAc (3×100 mL). The combined organic layers were washedwith water, brine and dried over Na₂SO₄ and concentrated under vacuum toget the crude material. The crude material was purified by columnchromatography using silica gel (60-120 mesh) and CHCl₃/MeOH as eluentto afford the title compound as an off white solid (3.2 g, 35% yield).¹H NMR (400 MHz, DMSO-d₆) δ 7.97-7.95 (dd, J=6.6, 1.9 Hz, 2H), 7.84-7.82(dd, J=6.7, 2.0 Hz, 2H), 6.52 (s, 1H), 2.79 (m, 2H), 1.30-1.24 (t, 3H).

Step 7: 4-(5-Ethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acidmethyl ester

A solution made of2-(4-bromo-phenyl)-5-ethyl-imidazo[5,1-b][1,2,4]oxadiazole (3.1 g, 10.6mmol) and triethylamine (3.7 mL, 26.0 mmol) in MeOH (50 mL) was degassedwith carbon monoxide. To this reaction mixture, 1,1-Bis diphenylphosphino ferrocene palladium(II)chloride (1:1 complex with DCM (0.9 g,1.0 mmol)) was added and heated to 60° C. for 18 h. After cooling to RT,the reaction mixture was filtered through a celite pad. The filtrate wasevaporated under reduced pressure and the residue purified with Et2O (50mL). The solid was filtered and dried under suction to afford the titlecompound (1.8 g, 64% yield) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.19-8.14 (m, 4H), 6.54 (s, 1H), 3.90 (s, 3H), 2.86-2.80 (m,2H) 1.39-1.27 (t, 3H). LC/MS (Method A): 272.0 (M+H)⁺. HPLC (Method F)Rt 2.6 min (Purity: 98.4%).

Intermediate 9:4-(5,7-Dimethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoic acid methylester

Step 1: 4-Hydrazinocarbonyl-Benzoic Acid Methyl Ester

Dimethyl terephthalate (19 g, 97 mmol) was taken in EtOH (200 mL) at25-26° C. under nitrogen atmosphere. Hydrazine hydrate (5.39 g, 107mmol) was added to the reaction mixture and stirred for 12 h at 90° C.(reaction completion was confirmed by TLC). The reaction mixture wascooled to 25-26° C. and concentrated to get crude product as white solid(20 g, 100% yield). The crude product was taken directly for next stepwithout further purification. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.96 (s, 1H),8.01-7.99 (m, 2H), 7.93-7.91 (m, 2H), 4.58 (b, 2H), 3.86 (s, 3H). LC/MS(Method A): 195.3 (M+H)⁺. HPLC (Method F) Rt 0.354 min (Purity: 70.3%)

Step 2: 4-[N′-(2-Acetylamino-propionyl)-hydrazinocarbonyl]-benzoic acidmethyl ester

4-Hydrazinocarbonyl-benzoic acid methyl ester (13 g, 66 mmol) was takenin DCM (100 mL) at 25-26° C. under nitrogen atmosphere. EDC-HCl (14.05g, 73 mmol), HOBT (9.9 g, 73 mmol) and triethylamine (20.2 g, 0.2 mol)were added and stirred for 15 minutes. N-acetyl alanine (9.60 g, 73mmol) was added to the reaction mixture and stirred for 12 h (reactioncompletion was confirmed by TLC). The reaction mixture was quenched withice water (50 mL) and stirred for 15 minutes. The precipitated solidswere filtered and dried to get the crude product as light brown solid.The crude product was directly taken for the next step without furtherpurification (12.3 g, 90% yield).

Step 3: 4-(5,7-Dimethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzoicacid methyl ester

4-[N′-(2-Acetylamino-propionyl)-hydrazinocarbonyl]-benzoic acid methylester (12.0 g, 40 mmol) was dissolved in MeCN (120 mL) at 25-26° C.under nitrogen atmosphere. POCl₃ (60 mL) was added slowly over 10minutes and the reaction mixture was heated to 110° C. for 12 h(reaction completion was confirmed by TLC). The reaction mixture wascooled to 25-26° C. and concentrated to get the brown liquid residue (20g). The residue was quenched with ice water (50 mL) and basified withsolid potassium carbonate and extracted with DCM (100 mL×2). The DCMlayer was washed with water (100 mL), brine solution (50 mL), dried oversodium sulphate and concentrated to get crude product as brown solid.The crude product was purified by column chromatography using 60-120mesh silica gel and 40% EtOAc in pet ether as eluent to get the productas a yellow solid (3.1 g, 30% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.12(s, 4H), 3.88 (s, 3H), 2.38 (s, 3H), 2.17 (s, 3H). LC/MS (Method B):272.0 (M+H)⁺. HPLC (Method F) Rt 2.61 min (Purity: 98.8%).

Intermediate 10:2-(4-Bromo-phenyl)-5-methyl-imidazo[5,1-b][1,2,4]oxadiazole

Step 1: 4-Bromobenzoic Acid Methyl Ester

4-Bromo benzoic acid (200 g, 994 mmol) was taken in CH₃OH (3 L) at25-26° C. under nitrogen atmosphere. SOCl₂ (591.5 g, 4.97 mol) was addedslowly over a period of 30 minutes. The reaction mixture was heated to80° C. and stirred for 12 h (reaction completion was confirmed byLC/MS). The reaction mixture was cooled to 25-26° C. and concentrated toget the crude product as white solid (250 g). The crude product wastaken in 10% NaHCO₃ solution (1 L) and stirred for 10 minutes, theprecipitated solids were filtered, washed with water (700 mL) and driedto get the pure product as white solid (194 g, 91% yield). ¹H NMR(DMSO-d₆, 400 MHz) δ 7.88-7.84 (m, 2H,), 7.74-7.70 (m, 2H), 3.84 (s,3H). HPLC (Method F) Rt 4.4 min (Purity: 99.1%).

Step 2: 4-Bromo-Benzoic Acid Hydrazide

4-Bromobenzoic acid methyl ester (200 g, 0.93 mol) was taken in EtOH(2.5 L) at 25-26° C. under nitrogen atmosphere. Hydrazine hydrate (232g, 4.65 mol) was added to the reaction mixture and stirred for 12 h at90° C. (reaction completion was confirmed by TLC). The reaction mixturewas cooled to 25-26° C. and concentrated to get crude product as whitesolid (176 g, 88% yield). The crude product was taken as such for thenext step without further purification. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.84(s, 1H), 7.76-7.73 (m, 2H), 7.66-7.63 (m, 2H), 4.42 (b, 2H). LC/MS(Method A): 217.0 (M+H)⁺. HPLC (Method F) Rt 2.02 min (Purity: 99.6%).

Step 3: N-{2-[N′-(4-Bromo-benzoyl)-hydrazino]-2-oxo-ethyl}-acetamide

4-Bromo-benzoic acid hydrazide (175 g, 0.81 mol) was taken in DCM (3 L)at 25-26° C. under nitrogen atmosphere. EDC-HCl (171 g, 0.89 mol), HOBt(120 g, 0.89 mol) and triethylamine (287 g, 2.83 mol) were added andstirred for 15 minutes. N-Acetyl glycine (104.27 g, 0.89 mol) was addedto the reaction mixture and stirred for 12 h (reaction completion wasconfirmed by TLC). The reaction mixture was quenched to ice water (1 L)and stirred for 15 minutes. The precipitated solids were filtered anddried to get the product as off-white solid (150 g, 59% yield). ¹H NMR(DMSO-d₆, 400 MHz) δ 10.43 (s, 1H) 9.98 (s, 1H), 8.22-8.19 (m, 1H),7.80-7.78 (m, 2H), 7.72-7.69 (m, 2H), 3.79 (b, 2H) 1.85 (s, 3H). LC/MS(Method A): 316.0 (M+H)+. HPLC (Method F) Rt 2.09 min (Purity: 99.7%).

Step 4: 2-(4-Bromo-phenyl)-5-methyl-imidazo[5,1-b][1,2,4]oxadiazole

N-{2-[N′-(4-Bromo-benzoyl)-hydrazino]-2-oxo-ethyl}-acetamide (100 g,0.317 mol) was dissolved in MeCN (1 L) at 25-26° C. under nitrogenatmosphere. POCl₃ (408 mL) was added slowly over 10 minutes and thereaction mixture was heated to 110° C. and stirred for 12 h (reactioncompletion was confirmed by TLC). The reaction mixture was cooled to25-26° C. and concentrated to get the brown liquid residue (107 g). Theresidue was quenched to ice water (750 mL) and basified with solidpotassium carbonate and extracted with DCM (1 L×2). The DCM layer waswashed with water (1 L), brine solution (500 mL), dried over Na₂SO₄ andconcentrated to get the crude product as brown solid. The crude productwas purified by column chromatography (60-120 mesh silica gel; eluent:40% EtOAc/pet ether) to get the product as yellow solid (47 g, 53%yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.96-7.93 (m, 2H), 7.84-7.81 (m,2H), 6.51 (s, 1H), 2.43 (s, 3H). LC/MS (Method A): 280.0 (M+H)+. HPLC(Method F) Rt 2.77 min (Purity: 99.6%).

Intermediate 11: 5-Methylimidazo[5,1-b][1,3,4]thiadiazole-2-carboxylicacid ethyl ester

Step 1: Hydrazino Carbonylmethyl-Carbamic Acid Tert-Butyl Ester

N-(tert-butoxycarbonyl)glycine methyl ester (78.12 mL, 529 mmol) wasdissolved in MeOH (200 mL) at 25° C. where upon a solution of hydrazinehydrate 100% (77.1 mL, 1586 mmol) was added to the solution. Thereaction mixture was heated to 80° C. and stirred for 1 hour at thistemperature (completion of the reaction was monitored by TLC). Thereaction mixture was cooled down to RT and MeOH was concentrated undervacuum to yield a residue that was re-dissolved in DCM (700 mL). Theorganic phase was washed with water (500 mL) and a saturated NaClsolution. The expected compound was extracted with DCM (5×400 mL).Combined organics were dried with MgSO₄ to yield after evaporation awhite solid (76 g, 76% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 8.95 (s, 1H),6.93 (t, J=6.0 Hz, 1H), 4.18 (s, 2H), 3.47 (d, J=6.2 Hz, 2H), 1.38 (s,9H). LC/MS (Method A): 216.0 (M+H)⁺. HPLC (Method F) Rt 1.02 min(Purity: 99.5%).

Step 2:5-(Tert-Butoxycarbonylamino-methyl)-[1,3,4]thiadiazole-2-carboxylic acidethyl ester

A suspension of hydrazino carbonylmethyl-carbamic acid tert-butyl ester(30 g, 158.6 mmol) and sodium bicarbonate (14 g, 166.5 mmol) in THF (300mL) under inert atmosphere was cooled down to 0° C. and treateddrop-wise with a solution of ethyl oxalyl chloride (18.63 mL, 166.5mmol) in THF (60 mL) over a period of 60 minutes keeping temperaturebelow 60° C. The reaction mixture was stirred at 0° C. for 2 hours andslowly warmed and stirred overnight at 25° C. (reaction completion wasconfirmed by TLC). The suspension was filtered and Lawesson's reagent(64.14 g, 159 mmol) was added to the filtrate. The resulting solutionwas heated at 50° C. for 4 hours until completion of the reaction. Thereaction was cooled down to RT, concentrated under vacuum and filteredover alumina (fast plug) eluting with EtOAc (100%) to give a yellowsolid that was used directly without further purification (29.6 g, 65%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (t, J=6.0 Hz, 1H), 4.57 (d,J=6.0 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 1.41 (s, 9H), 1.34 (t, J=7.1 Hz,3H). LC/MS (Method A): 288.2 (M+H)⁺.

Step 3: 5-[(acetylamino)methyl]-1,3,4-thiadiazole-2-carboxylic acidethyl ester

Under nitrogen atmosphere,5-(tert-butoxycarbonylamino-methyl)-[1,3,4]thiadiazole-2-carboxylic acidethyl ester (29.50 g, 102.7 mmol) was taken up in AcOH (885 mL). It washeated 24 hours at 115° C. until completion of the reaction (monitoredof the reaction by LC/MS). The reaction mixture was cooled to roomtemperature and stirred for two days. It was concentrated under vacuumand the expected compound precipitated by addition of MeCN (250 mL).After triturating at 25° C., a fine suspension was obtained and wasisolated by filtration, affording the title compound as a beige solid(23.8 g, 100% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (t, J=5.8 Hz,1H), 4.67 (d, J=6.8 Hz, 2H), 4.43 (q, J=7.1 Hz, 2H), 1.88 (s, 3H), 1.32(t, 3H).). LC/MS (Method A): 230.2 (M+H)⁺.

Step 4: 5-methylimidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acid ethylester

5-[(acetylamino)methyl]-1,3,4-thiadiazole-2-carboxylic acid ethyl ester(23.2 g, 101.2 mmol) was taken up in a mixture of MeCN (232 mL) andphosphorous oxychloride (27.87 mL, 303.6 mmol). The reaction mixture washeated at 80° C. for 4 hours until completion of the reaction. It wascooled to room temperature and concentrated under vacuum. The resultingresidue was taken in EtOAc (300 mL) and NaHCO₃ sat added slowly until pH8-9 (500 mL). The phases were separated. The aqueous phase was extractedwith EtOAc (3×250 mL) and the combined organics washed with brine (300mL), dried over MgSO₄, filtered and concentrated under vacuum to yield ayellow solid (20.56 g, 96% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.05 (s,1H), 4.45 (q, J=7.1 Hz, 2H), 2.61 (s, 3H), 1.36 (t, J=7.1 Hz, 3H). LC/MS(Method A): 212 (M+H)⁺. HPLC (Method F) Rt 1.32 min (Purity: 97.9%).

Intermediate 12: 5-Methylimidazo[5,1-b][1,3,4]thiadiazole-2-carboxylicacid

Intermediate 11 (20.5 g, 97.04 mmol) was saponified 30 minutes at roomtemperature in a mixture of THF (410 mL) and NaOH (194 mL, C=1.00 M,194.1 mmol). When the reaction was completed (the reaction was monitoredby LC/MS), it was concentrated under vacuum and water (150 mL) was addedto the reaction mass. The aqueous phase was washed with EtOAc (100 mL)and then acidified to pH 1 (HCl 1N, 250 mL) to afford a beige solid thatwas filtered off as HCl salt. It was dried under vacuum to yield thetitle compound as off-white solid (15.3 g, 72% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 12.45 (br s, 1H), 7.62 (s, 1H), 2.30 (s, 3H).

Intermediate 13:3-methoxy-4-(5-methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-phenylamine

Step 1: tert-butyl 2-hydrazinyl-2-oxoethylcarbamate

To a solution of N-(tert-butoxycarbonyl)-glycine methyl ester (21 g, 110mmol) in MeOH (100 mL), was added aqueous hydrazine hydrate (35% aqueoussolution, 16 mL, 184 mmol) in one portion. After 48 hours at 25° C. thereaction was concentrated under reduced pressure. The residual solventwas evaporated with dioxane and MeOH, and dried under vacuum at 40° C.for 16 hours to afford the title compound as a white crystalline solid(21 g, 100% yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 8.94 (s, 1H); 6.91 (t,J=6.17 Hz, 1H); 4.18 (s, 2H); 3.48 (d, J=6.15 Hz, 2H); 1.38 (s, 9H).

Step 2: 2-methoxy-4-nitrobenzoyl chloride

To a stirred suspension of benzoic acid (5 g, 25 mmol) in DCM (30 mL)was added DMF (5 drops) followed by oxalyl chloride (2.3 mL, 26.6 mmol).After 18 hours stirring at 25° C. the reaction was concentrated underreduced pressure and used immediately (25 mmol 100% yield).

Step 3: tert-butyl2-(2-(2-methoxy-4-nitrobenzoyl)hydrazinyl)-2-oxoethylcarbamate

To a stirred suspension of tert-butyl 2-hydrazinyl-2-oxoethylcarbamate(4.72 g, 25 mmol) and sodium hydrogen carbonate (2.1 g, 25 mmol) in THF(40 mL) at 0° C. was added a solution of 2-methoxy-4-nitrobenzoylchloride (25 mmol) in THF (10 mL) slowly and the reaction was allowed towarm to 25° C. After 4 hours, saturated aqueous sodium carbonatesolution (50 mL) was added and the product was extracted with ethylacetate (100 mL) and MeOH (20 mL). The combined organic layers werewashed with brine (50 mL) and concentrated under reduced pressure toafford the title compound as a pale yellow crystalline solid (8.7 g, 92%yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 10.22 (s, 2H); 7.93-7.87 (m, 2H);7.81-7.72 (m, 1H); 7.05 (t, J=6.18 Hz, 1H); 3.97 (s, 3H); 3.70-3.59 (m,2H); 1.40 (s, 9H).

Step 4: tert-butyl(5-(2-methoxy-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)methylcarbamate

To a stirred slurry of Lawesson's reagent (1.09 g, 2.7 mmol) in dry THF(12 mL) was added tert-butyl2-(2-(2-methoxy-4-nitrobenzoyl)hydrazinyl)-2-oxoethylcarbamate (1 g, 2.7mmol) under nitrogen. The reaction was sealed and heated at 60° C. for18 hours. The mixture was then cooled and concentrated under reducedpressure. The resulting crude residue was purified by chromatography(silica gel, isohexane/ethyl acetate) to afford the title compound as ayellow solid (600 mg, 59% yield). ¹H NMR (400 MHz, CHCl₃-d): δ 8.67 (d,J=8.67 Hz, 1H); 7.99 (dd, J=8.68, 2.14 Hz, 1H); 7.91 (d, J=2.13 Hz, 1H);5.31 (s, 1H); 4.80 (d, J=6.28 Hz, 2H); 4.13 (s, 3H); 1.49 (s, 9H).

Step 5:N-((5-(2-methoxy-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)methyl)acetamide

A solution of tert-butyl(5-(2-methoxy-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)methylcarbamate (600mg, 1.6 mmol) in acetic acid (10 mL) was stirred in a sealed tube at100° C. for 2 days. The reaction mixture was allowed to cool to 25° C.then concentrated under reduced pressure to afford the title compound asa brown solid (465 mg, 93% yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 8.84 (t,J=5.95 Hz, 1H); 8.56 (d, J=8.65 Hz, 1H); 8.06-7.99 (m, 2H); 4.71 (d,J=5.92 Hz, 2H); 4.16 (s, 3H); 1.91 (s, 3H).

Step 6:2-(2-methoxy-4-nitrophenyl)-5-methylimidazo[5,1-b][1,3,4]thiadiazole

To a stirred suspension ofN-((5-(2-methoxy-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)methyl)acetamide(465 mg, 1.5 mmol) in acetonitrile (10 mL) was added phosphorusoxychloride (1.07 mL, 1.76 g, 11.5 mmol) and the reaction was heated at60° C. for 18 hours. The reaction mixture was allowed to cool to 25° C.then concentrated under reduced pressure and used without furtherpurification (437 mg, 100% yield).

Step 7:3-methoxy-4-(5-methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-phenylamine

A slurry of nitrophenyl imidazothiadiazole (1.5 mmol) with iron powder(543 mg, 10.2 mmol) and ammonium chloride (164 mg 3.1 mmol) in THF (10mL)/EtOH (10 mL)/water (3 mL) was prepared. This reaction was sealedunder nitrogen and rapidly heated to 90° C. for 1 hour. The reaction wasallowed to cool to 25° C. then filtered through a celite pad and washedwith THF containing 5% MeOH. The organic phase was washed with diluteaqueous Na₂CO₃ solution, brine, dried (MgSO₄) and concentrated underreduced pressure to afford the title compound as a pale yellow powder(370 mg, 95% yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 7.88 (d, J=9.07 Hz,1H); 6.86 (s, 1H); 6.39-6.34 (m, 2H); 6.16 (s, 2H); 3.94 (s, 3H); 2.59(s, 3H).

Intermediate 14:4-(5-Methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-benzoic acid methylester

Step 1:4-[N′-(2-tert-Butoxycarbonylamino-acetyl)-hydrazinocarbonyl]-benzoicacid methyl ester

4-[N′-(2-tert-Butoxycarbonylamino-acetyl)-hydrazinocarbonyl]-benzoicacid methyl ester was prepared following the same protocol as forIntermediate 13, Steps 1 to 3, using 4-(chlorocarbonyl)benzoic acidmethyl ester. ¹H NMR (400 MHz, DMSO-d⁶): δ 10.56 (s, 1H); 10.01 (s, 1H);8.07 (d, J=8.14 Hz, 2H); 7.99 (d, J=8.17 Hz, 2H); 7.06 (t, J=6.16 Hz,1H); 3.90 (s, 3H); 3.67 (d, J=6.23 Hz, 2H); 1.40 (s, 9H).

Step 2:4-[5-(tert-Butoxycarbonylamino-methyl)-[1,3,4]thiadiazol-2-yl]-benzoicacid methyl ester

4-[5-(tert-Butoxycarbonylamino-methyl)-[1,3,4]thiadiazol-2-yl]-benzoicacid methyl ester was prepared following the same protocol as forIntermediate 13, Step 4, using4-[N′-(2-tert-Butoxycarbonylamino-acetyl)-hydrazinocarbonyl]-benzoicacid methyl ester. ¹H NMR (400 MHz, CHCl₃-d): δ 8.16-8.12 (m, 2H);8.05-8.01 (m, 2H); 5.30 (s, 1H); 4.76 (d, J=6.31 Hz, 2H); 3.96 (s, 3H);1.49 (s, 9H).

Step 3: 4-[5-(Acetylamino-methyl)-[1,3,4]thiadiazol-2-yl]-benzoic acidmethyl ester

4-[5-(Acetylamino-methyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methylester was prepared following the same protocol as for intermediate 13,Step 5, using4-[5-(tert-butoxycarbonylamino-methyl)-[1,3,4]thiadiazol-2-yl]-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d⁶): δ 8.88 (t, J=5.92 Hz, 1H);8.14-8.08 (m, 4H); 4.69 (d, J=5.92 Hz, 2H); 3.90 (s, 3H); 1.92 (s, 3H).

Step 4: 4-(5-Methylimidazo[5,1-b][1,3,4]thiadiazol-2-yl)benzoic acidmethyl ester

4-(5-Methylimidazo[5,1-b][1,3,4]thiadiazol-2-yl)benzoic acid methylester was prepared following the same protocol as for intermediate 13,Step 6, using 4-[5-(acetylamino-methyl)-[1,3,4]thiadiazol-2-yl]-benzoicacid methyl ester. The crude product was purified by chromatography(silica, isohexane/ethyl acetate) to afford the title compound as ayellow solid (450 mg, 95% yield). ¹H NMR (400 MHz, DMSO-d⁶): δ 8.15 (d,J=8.28 Hz, 2H); 8.09 (d, J=8.28 Hz, 2H); 7.00 (s, 1H); 3.91 (s, 3H);2.62 (s, 3H).

Intermediate 15:4-(5-Methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-phenylamine

Step 1: {2-[N′-(4-Nitro-benzoyl)-hydrazino]-2-oxo-ethyl}-carbamic acidtert-butyl ester

{2-[N′-(4-Nitro-benzoyl)-hydrazino]-2-oxo-ethyl}-carbamic acidtert-butyl ester was prepared following the same protocol as forintermediate 13, Steps 1 to 3, using 4-nitrobenzoyl chloride. ¹H NMR(400 MHz, DMSO-d⁶): δ 10.74 (s, 1H); 10.10 (s, 1H); 8.34 (d, J=8.63 Hz,2H); 8.14-8.06 (m, 2H); 7.10 (t, J=6.16 Hz, 1H); 3.67 (d, J=6.21 Hz,2H); 1.40 (s, 9H).

Step 2: [5-(4-Nitro-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-carbamic acidtert-butyl ester

[5-(4-Nitro-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-carbamic acidtert-butyl ester was prepared following the same protocol as forintermediate 13, Step 4, using{2-[N′-(4-Nitro-benzoyl)-hydrazino]-2-oxo-ethyl}-carbamic acidtert-butyl ester. ¹H NMR (400 MHz, CHCl₃-d): δ 8.38-8.30 (m, 2H);8.16-8.12 (m, 2H); 5.40 (s, 1H); 4.80 (d, J=5.14 Hz, 2H); 1.49 (s, 9H).

Step 3: N-[5-(4-Nitro-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-acetamide

N-[5-(4-Nitro-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-acetamide wasprepared following the same protocol as intermediate 13, step 5, using[5-(4-Nitro-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-carbamic acidtert-butyl ester. ¹H NMR (400 MHz, CHCl₃-d): δ 8.38-8.31 (m, 2H);8.17-8.10 (m, 2H); 6.33 (s, 1H); 4.89 (d, J=6.03 Hz, 2H); 2.09 (s, 3H).

Step 4: 4-(5-Methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-phenylamine

4-(5-methylimidazo[5,1-b][1,3,4]thiadiazol-2-yl)aniline was preparedfollowing the same protocol as intermediate 13, Steps 6 and 7, usingN-[5-(4-Nitro-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-acetamide. It wasisolated as a yellow solid. ¹H NMR (400 MHz, DMSO-d⁶): δ 7.58 (t, J=8.35Hz, 2H); 6.88 (s, 1H); 6.71-6.64 (m, 2H); 6.05 (s, 2H); 2.54 (s, 3H).

Example 1:N-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-2-(2-trifluoromethyl-phenyl)-acetamide

To a solution of 2-(trifluoromethyl)phenylacetic acid (80 mg; 0.39 mmol)in DCE (8 mL) were added N,N-diisopropylethylamine (0.14 mL; 0.78 mmol)and HATU (149 mg; 0.39 mmol). The solution was stirred at roomtemperature for 30 minutes. Intermediate 4 (125.9 mg; 0.59 mmol) wasadded and the reaction was stirred at room temperature overnight. It wasthen diluted with DCM (20 mL) and was washed with NaHCO₃ sat (15 mL),water (15 mL) and brine (15 mL). Organic phase was dried over MgSO₄,filtered and evaporated under vacuo. The crude product was purified byflash chromatography (EtOAc/MeOH gradient from 100:0 to 80:20) then byMD Autoprep, affording the title compound as white foam (30 mg, 19%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.00 (d, J=8.8 Hz,2H), 7.83 (d, J=8.85 Hz, 2H), 7.78-7.61 (m, 2H), 7.61-7.45 (m, 2H), 6.52(s, 1H), 4.00 (brs, 2H), 2.44 (s, 3H). LC/MS (Method A): 401.1 (M+H)⁺.HPLC (Method F) Rt 3.25 min (Purity: 96.7%).

Example 2:N-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-2-m-tolyl-acetamide

To a solution of meta-tolylacetic acid (80 mg; 0.53 mmol) in DCE (8 mL)was added T3P solution (50% in EtOAc, 0.22 mL; 0.80 mmol) andtriethylamine (0.074 mL; 0.53 mmol). The solution was stirred at 0° C.for 30 minutes. Intermediate 4 (171.2 mg; 0.80 mmol) was added and thereaction mixture was stirred at 60° C. overnight. It was then dilutedwith DCM (20 mL) and was washed with NaHCO₃ sat (15 mL), water (15 mL)and brine (15 mL). Organic phase was dried over MgSO₄, filtered andevaporated under vacuo. The crude product was purified by flashchromatography (EtOAc/MeOH gradient from 100:0 to 80:20) then by MDAutoprep, affording the title compound as white solid (32 mg, 17%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.00 (d, J=8.8 Hz,2H), 7.85 (d, J=8.8 Hz, 2H), 7.27-7.01 (m, 4H), 6.5 (s, 1H), 3.66 (s,2H), 2.44 (s, 3H), 2.30 (s, 3H). LC/MS (Method A): 347.12 (M+H)⁺. 345.05(M−H)⁻. HPLC (Method F) Rt 2.81 min (Purity: 99.3%).

Example 3:N-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-2-(3-trifluoromethyl-phenyl)-acetamide

Oxalyl chloride (889 mg; 7 mmol) was added to a solution of3-(trifluoromethyl)phenylacetic acid (428.8 mg; 2.1 mmol) and DMF (0.005mL) in DCM (15 mL) and the resulting mixture was stirred at roomtemperature for 1 hour. It was concentrated in vacuo and the residue wastaken up in DCM (2 mL) and added to a suspension of Intermediate 4 (150mg; 0.70 mmol) in DMF (5 mL) and N,N-diisopropylethylamine (108.6 mg;0.84 mmol). The reaction mixture was stirred at room temperature for 4hours. It was then diluted with DCM (20 mL), washed with NaHCO₃ sat(2×15 mL), brine (15 mL), dried over Na₂SO₄ and concentrated in vacuo togive the crude product as a yellow oil. It was crystallized in hot MeCN,affording the title product as beige solid (148 mg, 53% yield). ¹H NMR(300 MHz, DMSO-d₆) δ 10.65 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.84 (d,J=8.8 Hz, 2H), 7.72 (br s, 1H), 7.68-7.54 (m, 3H), 6.49 (s, 1H), 3.86(s, 2H), 2.43 (s, 3H). LC/MS (Method A): 401.17 (M+H)⁺. HPLC (Method F)Rt 3.21 min (Purity: 99.8%).

Example 4:2-(4-Chloro-3-trifluoromethyl-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide

Oxalyl chloride (133 mg; 1.05 mmol) was added to a solution of4-chloro-3-(trifluoromethyl)phenylacetic acid (50 mg; 0.21 mmol) and DMF(0.005 mL) in DCM (6 mL) at 0° C. under inert atmosphere and theresulting mixture was stirred at 0° C. for 1 hour. It was concentratedin vacuo and the residue was taken up in DCM (6 mL).N,N-diisopropylethylamine (72.23 μl; 0.42 mmol) and Intermediate 4(67.34 mg; 0.31 mmol) were added and the mixture was stirred at roomtemperature overnight. It was then diluted with DCM (20 mL), washed withNaHCO₃ sat (2×15 mL), brine (15 mL), dried over MgSO₄ and concentratedin vacuo to give the crude product as white solid. It was purified by MDAutoprep affording the title compound as white solid (15 mg, 16% yield).¹H NMR (DMSO-d₆, 300 MHz) δ 10.68 (s, 1H), 8.00 (d, J=8.91 Hz, 2H), 7.84(d, J=8.88 Hz, 2H), 7.75-7.60 (m, 3H), 6.50 (s, 1H), 3.88 (s, 2H), 2.44(s, 3H). LC/MS (Method A): 435.02 (M+H)⁺. 433.03 (M−H)⁻. HPLC (Method F)Rt 3.52 min (Purity: 98.6%).

Example 5:2-(2-Bromo-4-trifluoromethyl-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide

To a solution of 2-bromo-4-(trifluoromethyl)phenylacetic acid (126.84mg; 0.45 mmol) in dry DMF (2 mL) in a MW vial, was added T3P (50%solution in EtOAc, 0.15 mL; 0.56 mmol) and triethylamine (0.05 mL; 0.37mmol) at 0° C. under inert atmosphere. The solution was stirred for 1hour at room temperature. A solution of Intermediate 4 (80 mg; 0.37mmol) in DMF (1 mL) was then added and the resulting mixture was stirredat 100° C. overnight. The reaction mixture was cooled down to roomtemperature, EtOAc (20 mL) was added and the solution was washed withNaHCO₃ sat (15 mL), water (15 mL), brine (15 mL) and dried over MgSO₄.After filtration and evaporation of the solvents, yellow oil wasobtained. It was purified by MD Autoprep, affording the title compoundas a white solid (16 mg, 9% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 10.75(s, 1H), 8.05-7.96 (m, 3H), 7.90-7.81 (d, J=8.9 Hz, 2H), 7.80-7.75 (m,1H), 7.68 (d, J=8.02 Hz, 1H), 6.51 (s, 1H), 4.05 (brs, 2H), 2.44 (s,3H). LC/MS (Method A): 481.00 (M+H)⁺. 479.02 (M−H)⁻. HPLC (Method F) Rt4.13 min (Purity: 97.6%).

Example 6:N-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-2-(4-trifluoromethoxy-phenyl)-acetamide

To a solution of 4-(trifluoromethoxy)phenylacetic acid (106.88 mg; 0.49mmol) in dry DMF (2 mL) in a MW vial, was added T3P (50% solution inEtOAc, 0.15 mL; 0.56 mmol) and triethylamine (0.05 mL; 0.37 mmol) at 0°C. under inert atmosphere. The solution was stirred for 1 hour at roomtemperature. A solution of Intermediate 4 (80 mg; 0.37 mmol) in DMF (1mL) was then added and the resulting mixture was stirred at 100° C.overnight. The reaction mixture was cooled down to room temperature,EtOAc (20 mL) was added and the solution was washed with NaHCO₃ sat (15mL), water (15 mL), brine (15 mL) and dried over MgSO₄. After filtrationand evaporation of the solvents, yellow oil was obtained. It waspurified by MD Autoprep, affording the title compound as a white solid(64 mg, 41% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 10.64 (s, 1H), 8.00 (d,J=8.82 Hz, 2H), 7.84 (d, J=8.84 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.34(d, J=8.1 Hz, 2H), 6.50 (s, 1H), 3.77 (s, 2H), 2.44 (s, 3H). LC/MS(Method A): 417.07 (M+H)⁺. 415.06 (M−H)⁻. HPLC (Method F) Rt 3.34 min(Purity: 99.5%).

Example 7:2-(4-Chloro-2,6-difluoro-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide

The title compound was prepared following the same procedure as Example6, starting with 4-chloro-2,6-difluorophenylacetic acid (115.71 mg; 0.56mmol). It was isolated as white solid (32 mg, 21% yield). ¹H NMR(DMSO-d₆, 300 MHz) δ 10.75 (s, 1H), 8.01 (d, J=8.85 Hz, 2H), 7.82 (d,J=8.86 Hz, 2H), 7.47-7.36 (m, 2H), 6.50 (s, 1H), 3.84 (s, 2H), 2.44 (s,3H). LC/MS (Method A): 403.0 (M+H)⁺. 401.0 (M−H)⁻. HPLC (Method F) Rt3.08 min (Purity: 97.6%).

Example 8:2-(4-Ethoxy-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide

The title compound was prepared following the same procedure as Example6, starting with 4-ethoxyphenylacetic acid (100.9 mg; 0.56 mmol). It wasisolated as white solid (73 mg, 52% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ10.54 (s, 1H), 7.99 (d, J=8.72 Hz, 2H), 7.84 (d, J=8.66 Hz, 2H), 7.24(d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 6.5 (s, 1H), 3.99 (q, J=7.08,7.17 Hz, 2H), 3.62 (s, 2H), 2.44 (s, 3H), 1.31 (tr, J=6.91 Hz, 3H).LC/MS (Method A): 377.12 (M+H)⁺. 375.10 (M−H)⁻. HPLC (Method F) Rt 2.80min (Purity: 97.4%).

Example 9:2-(3-Bromo-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide

The title compound was prepared following the same procedure as Example6, starting with 3-bromophenylacetic acid (180.69 mg; 0.84 mmol). It wasisolated as white solid (23 mg, 8% yield). ¹H NMR (DMSO-d₆, 300 MHz)) δ10.62 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H), 7.57 (s,1H), 7.51-7.42 (m, 1H), 7.39-7.24 (m, 2H), 6.50 (s, 1H), 3.74 (s, 2H),2.44 (s, 3H). LC/MS (Method A): 412.97 (M+H)⁺. 411.03 (M−H)⁻. HPLC(Method F) Rt 3.63 min (Purity: 93.9%).

Representative Method A

A solution of Intermediate 5 (80 mg, 0.37 mmol, 1 equiv) indichloromethane (4 mL) and tetrahydrofuran (1 mL) was mixed with HATU(212.0 mg, 0.5579 mmol, 1.5 equiv) and the appropriate carboxylic acidof formula (V) (1.5 equiv), DIPEA (0.19 mL, 1.12 mmol, 3 equiv) wasadded to the reaction mixture. The reaction mixture was stirred at roomtemperature for about 2 days in orbital shaker. The reaction mixture wasconcentrated to remove the solvent, then diluted with water (20 mL) andextracted with dichloromethane (2×20 mL), combined organic layer waswashed with brine solution (1×20 mL), dried over anhydrous sodiumsulphate, filtered and evaporated under reduced pressure. The cruderesidue was purified by column chromatography using petroleumether-ethyl acetate as eluents to get the product.

The following compounds were prepared using representative method A withintermediate 5 and an appropriate carboxylic acid of formula (V):

Ex HPLC Rt No Structure (Appareance) (% Purity) MS NMR 10

3.37^(f) (99.1%) 362.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.78 (s,1H), 8.93 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (d,J = 8.7 Hz, 1H), 7.06 (d, J = 4.5 Hz, 2H), 6.97 (d, J = 7.7 Hz, 1H),6.52 (s, 1H), 3.73 (s, 2H), 2.45 (s, 3H), 2.24 (s, 6H)2-(2,5-Dimethyl-phenyl)-N-[6-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-acetamide (Off-white solid) 11

3.75^(f) (98.4%) 418.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.85 (s,1H), 8.92-8.92 (m, 1H), 8.32 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (d, J = 8.7Hz, 1H), 7.45-7.49 (m, 2H), 7.33- 7.35 (m, 2H), 6.52 (s, 1H), 3.84 (s,2H), 2.44 (s, 3H)N-[6-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-2-(4-trifluoromethoxy-phenyl)-acetamide (Off-white solid) 12

3.66^(f) (98.7%) 402.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.83 (s,1H) ,8.92 (t, J = 2.0 Hz, 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (d,J = 8.6 Hz, 1H), 7.59-7.63 (m, 2H), 7.34 (dd, J = 8.3, 2.0 Hz, 1H), 6.52(s, 1H), 3.80 (s, 2H), 2.44 (s, 3H)2-(3,4-Dichloro-phenyl)-N-[6-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-acetamide (Off-white solid) 13

3.58^(f) (96.9%) 384.3 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.99 (s,1H), 8.95 (t, J = 2.0 Hz, 1H), 8.31-8.34 (m, 1H), 8.09-8.15 (m, 2H),7.94-7.96 (m, 1H), 7.85-7.88 (m, 1H), 7.47-7.59 (m, 4H), 6.51 (s, 1H),4.25 (s, 2H), 2.44 (s, 3H)N-[6-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-2-naphthalen-1-yl-acetamide (Off-white solid) 14

3-59^(f) (99.1%) 402.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.87 (s,1H), 8.92 (t, J = 0.5 Hz, 1H), 8.32 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (d,J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.63-7.66 (m, 2H), 7.56-7.60 (m, 1H),6.52 (s, 1H), 3.90 (s, 2H), 2.44 (s, 3H)N-[6-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-2-(3-trifluoromethyl-phenyl)-acetamide (Off-white solid) 15

3.86^(f) (99.2%) 426.2 (M + H)⁺N-[6-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-2-(3-phenoxy-phenyl)-acetamide (Yellow solid) 16

3.76^(f) (97.8%) 422   (M + H)⁺4-Fluoro-N-[6-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-3-trifluoromethoxy-benzamide (Off-white solid)^(a-f)Rt refers to HPLC methods A to F

Representative Method B

Bis(trimethylaluminum)-1,4-diazabicyclo(2.2.2)octane adduct (DABAL-Me₃,267 mg, 1.04 mmol, 1.5 equiv) and appropriate amine of formula (III)(1.04 mmol, 1.5 equiv) in anhydrous THF (3 mL) were taken in 10 mLmicrowave vial. It was heated up to 130° C. for 20 min. ThenIntermediate 7 (199 mg, 0.69 mmol, 1 equiv) was added and the reactionmixture stirred at 130° C. for another 30 min. Reaction mixture wasallowed to cool to room temperature, quenched by the addition of 2M HCl.Reaction mixture was extracted with ethyl acetate. Organic layer wasdried over anhydrous sodium sulphate and evaporated under reducedpressure. The crude residue was purified by column chromatography usingpetroleum ether-ethyl acetate as eluents to get the pure amide.

The following compounds were prepared using representative method B,with intermediate 7 and an appropriate amine of formula (III):

Ex HPLC Rt No Structure (Appearance) (% Purity) MS NMR 18

3.70^(f) (94.9%) 431.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆): δ 9.37 (t, J= 6.0 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.57-7.73 (m, 6H), 6.50 (s,1H), 4.60 (d, J = 5.9 Hz, 2H), 4.00 (s, 3H), 2.45 (s, 3H)3-Methoxy-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-N-(3-trifluoromethyl-benzyl)-benzamide (White solid) 19

3.77^(f) (96.8%) 431.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J= 5.9 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H),7.62-7.66 (m, 1H), 7.60 (d, J = 1.6 Hz, 2H), 7.34 (dd, J = 8.3, 2.0 Hz,1H), 6.50 (s, 1H), 4.50 (d, J = 5.8 Hz, 2H), 4.00 (s, 3H), 2.45 (s, 3H)N-(3,4-Dichloro-benzyl)-3-methoxy-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-benzamide (Off-white solid) 20

3.60^(f) (99.1%) 413.0 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d⁶): δ 9.30 (t, J= 5.8 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.95-8.01 (m, 2H), 7.86-7.88(m, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.67-7.69 (m, 1H), 7.51-7.60 (m, 4H),4.99 (d, J = 5.6 Hz, 2H), 3.31 (s, 3H), 2.44 (s, 3H)3-Methoxy-4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-N-naphthalen-1-ylmethyl-benzamide (Off-white solid) ^(a-f)Rt refers toHPLC methods A to F

Representative Method C

Bis(trimethylaluminum)-1,4-diazabicyclo(2.2.2)octane adduct (DABAL-Me₃,267 mg, 1.04 mmol, 1.5 equiv) and appropriate amine of formula (III)(1.04 mmol, 1.5 equiv) in anhydrous THF (3 mL) were taken in 10 mLmicrowave vial. It was heated up to 130° C. for 20 min. ThenIntermediate 8 (187 mg, 0.69 mmol, 1 equiv) was added and the reactionmixture stirred at 130° C. for another 30 min. Reaction mixture wasallowed to cool to room temperature, quenched by the addition of 2M HCl.Reaction mixture was extracted with ethyl acetate. Organic layer wasdried over anhydrous sodium sulphate and evaporated under reducedpressure. The crude residue was purified by column chromatography usingpetroleum ether-ethyl acetate as eluents to get the pure amide.

The following compound was prepared from intermediate 8 following methodC, using appropriate amine of formula (III):

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 21

3.86^(f) (99.3%) 397.3 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.31 (t, J= 5.8 Hz, 1H), 8.20 (d, J = 1.0 Hz, 1H), 8.10- 8.18 (m, 4H), 7.95-7.97(m, 1H), 7.86 (dd, J = 7.6, 1.7 Hz, 1H), 7.47-7.60 (m, 4H), 6.54 (s,1H), 4.98 (d, J = 5.7 Hz, 2H), 2.83 (q, J = 7.6 Hz, 2H), 1.29 (t, J =7.6 Hz, 3H). 4-(5-Ethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-N-naphthalen-1-ylmethyl-benzamide (Off-white solid) ^(a-f)Rt refers toHPLC methods A to F

Representative Method D

Trimethylaluminium (2M solution in THF, 0.41 mL, 0.81 mmol) was addeddrop-wise to a cold (0° C.) solution of amine of formula (III) (142 mg,0.81 mmol) in DCE (10 mL). The resulting mixture was stirred at 0° C.for 30 minutes whereupon a solution of Intermediate 9 (100 mg, 0.37mmol) in DCE (10 mL) was added. The reaction mixture was stirred at roomtemperature for 1 hour then 3 hours at 70° C. before being quenched withwater (20 mL). The DCE phase was washed with aqueous Rochelle's salt(2×20 mL), brine (20 mL) and finally dried over sodium sulfate andconcentrated in vacuo to yield a yellow oil. The crude material waspurified by flash column chromatography (60-120 mesh silica gel; eluent:40% EtOAc in DCM) affording the expected compound as a solid.

The following compounds were prepared using representative method D withintermediate 9 and an appropriate amine of formula (III):

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 22

3.62^(f) (95.7%) 397.1  (M + H)⁺ ¹H NMR (300 MHz, DMSO-d⁶): δ 8.14 (d, J= 7 Hz, 3H), 7.99-7.86 (m, 4H), 7.63-7.45 (m, 4H), 6.54-6.49 (m, 1H),5.15 (d, J = 6.5 Hz, 2H), 2.65 (s, 3H), 2.40 (s, 3H)4-(5,7-Dimethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-N-naphthalen-1-ylmethyl-benzamide (White solid) 23

3.63^(f) (99.8%) 415.06 (M + H)⁺ ¹H NMR (300 MHz, DMSO-d⁶): δ 8.13 (d, J= 7.5 Hz, 2H), 8.07 (d, J = 7.5 Hz, 2H), 7.65-7.60 (m, 2H), 7.54-7.47(m, 1H), 7.47-7.41 (m, 1H), 6.98-6.91 (m, 1H), 4.86 (d, J = 6.5 Hz, 2H),2.51 (s, 3H), 2.31 (s, 3H)4-(5,7-Dimethyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-N-(2-trifluoromethyl-benzyl)-benzamide (White solid) ^(a-f)Rt refers to HPLCmethods A to F

Representative Method E

A carousel tube was charged with Intermediate 1 (100 mg, 0.358 mmol), anamine of formulate (III) (0.358 mmol), Pd₂dba₃ (16 mg, 0.017 mmol),xantphos (31 mg, 0.057 mmol) and Cs₂CO₃ (116 mg, 0.358 mmol). Dioxane (3mL) was added and nitrogen was bubbled through the mixture for 5minutes. The carousel tube was sealed and the reaction was stirred at110° C. overnight. The reaction mixture was allowed to cool to 25° C.and then partitioned between DCM (30 mL) and water (25 mL). The organicphase was collected and the aqueous phase was extracted with DCM (2×30mL). The combined organic extracts were dried (MgSO₄), filtered, andevaporated to dryness under vacuum. The crude residue was dissolved inDMSO and purified by preparative HPLC.

The following compound was prepared from intermediate 1 following methodE, using appropriate amine of formula (III):

Ex HPLC Rt No Structure (Appareance) (% Purity) MS NMR 28

2.87^(b) (97.9%) 374 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 8.18 (d, J =2.76 Hz, 1H); 7.86 (d, J = 8.73 Hz, 1H); 7.68-7.60 (m, 2H), 7.54 (t, J =6.18 Hz, 1H); 7.37 (dd, J = 8.28, 2.05 Hz, 1H); 7.04 (dd, J = 8.77, 2.80Hz, 1H); 6.46 (s, 1H); (3,4-Dichloro-benzyl)-[6-(5-methyl-imidazo[5,1-4.46 (d, J = 6.13 Hz, 2H); b][1,2,4]oxadiazol-2-yl)-pyridin-3-yl]-amine(Brown solid) 2.42 (s, 3H). ^(a-f)Rt refers to HPLC methods A to F

Representative Method F

A carousel tube was charged with an acid of formula (V) (0.275 mmol), asolution of an amine of formula (IV) (0.25 mmol) in DMF (0.75 mL) and asolution of HATU (95 mg, 0.25 mmol) in DMF (0.5 mL). Hunig's base (43μL, 0.25 mmol) was added and the carousel tube was sealed. After 16hours at 25° C., the reaction mixture was purified directly bypreparative HPLC.

The following compounds were prepared using representative method F withintermediate 2 and an appropriate acid of formula (V):

Ex HPLC Rt No Structure (Appareance) (% Purity) MS NMR 37

3.23^(a) (97.6%) 431 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.65 (s,1H); 7.86 (d, J = 8.60 Hz, 1H); 7.73 (d, J = 7.92 Hz, 1H); 7.71-7.65 (m,2H); 7.57-7.48 (m, 2H); 7.31 (dd, J = 8.63, 1.86 Hz, 1H); 6.47 (s, 1H);4.00 (s, 2H); 3.89 (s, 3H); 2.44 (s, 3H).N-(3-methoxy-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(2- (trifluoromethyl)phenyl)acetamide(Off-white solid) 36

2.96^(a) (98.4%) 363 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.59 (s,1H); 7.85 (d, J = 8.60 Hz, 1H); 7.67 (d, J = 1.85 Hz, 1H); 7.38-7.32 (m,5H); 7.29-7.24 (m, 1H); 6.46 (s, 1H); 3.90 (s, 3H); 3.71 (s, 2H); 2.43(s, 3H). N-(3-methoxy-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-phenylacetamide (Off-white solid) 35

3.57^(a) (98.8%) 407 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.53 (s,1H); 7.84 (d, J = 8.60 Hz, 1H); 7.66 (d, J = 1.84 Hz, 1H); 7.35 (dd, J =8.63, 1.86 Hz, 1H); 7.25 (d, J = 8.48 Hz, 2H); 6.91-6.87 (m, 2H); 6.46(s, 1H); 4.00 (q, J = 6.98 Hz, 2H); 3.89 (s, 3H); 3.62 (s, 2H); 2.43 (s,2H); 1.32 (t, J = 6.96 Hz, 3H).2-(4-ethoxyphenyl)-N-(3-methoxy-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 34

3.34^(a) (98.4%) 447 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.63 (s,1H); 7.85 (d, J = 8.60 Hz, 1H); 7.67 (d, J = 1.85 Hz, 1H); 7.47 (d, J =8.49 Hz, 2H); 7.36-7.31 (m, 3H); 6.46 (s, 1H); 3.90 (s, 3H); 3.78 (s,2H); 2.43 (s, 3H).N-(3-methoxy-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (Off-white solid) 33

3.67^(a) (98.6%) 397 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.61 (s,1H); 7.86 (d, J = 8.60 Hz, 1H); 7.66 (d, J = 1.85 Hz, 1H); 7.43 (s, 1H);7.40-7.28 (m, 4H); 6.46 (s, 1H); 3.90 (s, 3H); 3.75 (s, 2H); 2.43 (s,3H). 2-(3-chlorophenyl)-N-(3-methoxy-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 32

4.08^(a) (98.7%) 499 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.85 (s,1H); 7.99 (s, 2H); 7.87 (d, J = 8.59 Hz, 1H); 7.67 (d, J = 1.84 Hz, 1H);7.29 (dd, J = 8.60, 1.88 Hz, 1H); 6.47 (s, 1H); 4.21 (s, 2H); 3.89 (s,3H); 2.44 (s, 3H).2-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(3-methoxy-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-whitesolid) 31

3.31^(a) (98.5%) 431 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.65 (s,1H); 7.86 (d, J = 8.61 Hz, 1H); 7.72 (s, 1H); 7.67 (s, 2H); 7.64 (s,1H); 7.60 (d, J = 7.60 Hz, 1H); 7.34 (dd, J = 8.63, 1.86 Hz, 1H); 6.46(s, 1H); 3.90 (s, 3H); 3.87 (s, 2H); 2.43 (s, 3H).N-(3-methoxy-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (Off-white solid)^(a-f)Rt refers to HPLC methods A to F

The following compounds were prepared using representative method F withintermediate 3 and an appropriate acid of formula (V):

Ex HPLC Rt No Structure (Appareance) (% Purity) MS NMR 46

4.00^(a) (99.0%) 429 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.71 (s,1H); 7.89 (d, J = 2.06 Hz, 1H); 7.84 (dd, J = 8.48, 2.16 Hz, 1H); 7.79(s, 1H); 7.73 (t, J = 7.61 Hz, 2H); 7.68-7.58 (m, 2H); 6.50 (s, 1H);4.16 (q, J = 7.01 Hz, 1H); 2.44 (s, 3H); 2.32-2.20 (m, 3H); 1.50 (d, J =6.99 Hz, 3H). N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)propanamide (Yellow solid) 45

3.83^(a) (97.6%) 431 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.72 (s,1H); 7.92 (s, 1H); 7.85 (s, 2H); 7.50 (d, J = 8.21 Hz, 2H); 7.35 (d, J =8.16 Hz, 2H); 6.66 (s, 1H); 3.83 (s, 2H); 2.49 (s, 3H); 2.34 (s, 3H).N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (White solid) 44

2.44^(b) (96.4%) 381 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.70 (s,1H); 7.91 (s, 1H); 7.86-7.79 (m, 2H); 7.44- 7.37 (m, 4H); 6.50 (s, 1H);3.78 (s, 2H); 2.44 (s, 3H); 2.33 (s, 3H).2-(4-chlorophenyl)-N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 43

10.07^(c)  (97.3%) 381 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.71 (s,1H); 7.91 (s, 1H); 7.87-7.80 (m, 2H); 7.46 (s, 1H); 7.41-7.31 (m, 3H);6.51 (s, 1H); 3.80 (s, 2H); 2.45 (s, 3H); 2.34 (s, 3H).2-(3-chlorophenyl)-N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 42

3.33^(b) (98.2%) 483 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.94 (s,1H); 7.98 (s, 2H); 7.93 (s, 1H); 7.85 (dd, J = 8.52, 2.09 Hz, 1H); 7.79(d, J = 8.50 Hz, 1H); 6.51 (s, 1H); 4.26 (s, 2H); 2.45 (s, 3H); 2.39 (s,3H). 2-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-whitesolid) 41

3.71^(a) (98.2%) 415 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.75 (s,1H); 7.91 (s, 1H); 7.87-7.80 (m, 2H); 7.75 (s, 1H); 7.71-7.55 (m, 3H);6.50 (s, 1H); 3.91 (s, 2H); 2.44 (s, 3H); 2.34 (s, 3H).N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (Off-white solid) 40

2.95^(b) (99.6%) 415 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.74 (s,1H); 7.92 (s, 1H); 7.85 (dd, J = 8.54, 2.09 Hz, 1H); 7.80 (d, J = 8.50Hz, 1H); 7.73 (d, J = 7.92 Hz, 1H); 7.67 (t, J = 7.59 Hz, 1H); 7.56 (d,J = 7.70 Hz, 1H); 7.51 (t, J = 7.68 Hz, 1H); 6.51 (s, 1H); 4.05 (s, 2H);2.45 (s, 3H); 2.37 (s, 3H).N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (Off-white solid) 39

3.46^(a) (98.5%) 415 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.76 (s,1H); 7.91 (s, 1H); 7.88-7.79 (m, 2H); 7.72 (d, J = 8.03 Hz, 2H); 7.60(d, J = 7.97 Hz, 2H); 6.50 (s, 1H); 3.90 (s, 2H); 2.44 (s, 3H); 2.34 (s,3H). N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide (Off-white solid) 38

3.57^(a) (98.0%) 375 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.59 (s,1H); 7.91 (s, 1H); 7.84 (d, J = 1.30 Hz, 2H); 7.12-7.03 (m, 2H); 6.98(d, J = 7.74 Hz, 1H); 6.50 (s, 1H); 3.76 (s, 2H); 2.45 (s, 3H); 2.34 (s,3H); 2.27 (s, 3H); 2.26 (s, 3H).2-(2,5-dimethylphenyl)-N-(2-methyl-4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) ^(a-f)Rtrefers to HPLC methods A to F

The following compounds were prepared using representative method F withintermediate 4 and an appropriate acid of formula (V):

Ex HPLC Rt No Structure (Appareance) (% Purity) MS NMR 77

2.62^(a) (96.1%) 401 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.62 (s,1H); 8.00 (d, J = 8.67 Hz, 2H); 7.84 (d, J = 8.67 Hz, 2H); 7.65-7.59 (m,2H); 7.34 (dd, J = 8.28, 2.06 Hz, 1H); 6.50 (s, 1H); 3.77 (s, 2H); 2.44(s, 3H). 2-(3,4-dichlorophenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 73

4.00^(a) (95.3%) 423 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.70 (s,1H); 8.08- 7.97 (m, 4H); 7.86 (d, J = 8.47 Hz, 2H); 7.74 (s, 1H); 7.42(d, J = 8.65 Hz, 1H); 6.50 (s, 1H); 4.01 (s, 2H); 2.44 (s, 3H).2-(5-chlorobenzo[b]thiophen-3-yl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 71

3.83^(a) (98.3%) 383 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d⁶): δ 10.76 (s,1H); 8.12 (d, J = 8.29 Hz, 1H); 8.02-7.92 (m, 3H); 7.88-7.83 (m, 3H);7.61-7.46 (m, 4H); 6.51 (s, 1H); 4.22 (s, 2H); 2.44 (s, 3H).N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(naphthalen-1-yl)acetamide (Off-white solid) 70

3.15^(b) (98.1%) 439 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.58 (s,1H); 8.03- 7.96 (m, 2H); 7.88-7.82 (m, 2H); 7.46-7.28 (m, 6H); 7.25 (t,J = 7.90 Hz, 1H); 7.02 (d, J = 2.14 Hz, 1H); 6.95-6.89 (m, 2H); 6.50 (s,1H); 5.13-5.04 (m, 2H); 3.68 (s, 2H); 2.44 (s, 3H).2-(3-(benzyloxy)phenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 69

9.85^(c) (95.1%) 415 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.72 (s,1H); 8.03- 7.97 (m, 2H); 7.86-7.80 (m, 2H); 7.29 (dd, J = 8.95, 1.75 Hz,1H); 7.16 (t, J = 8.99 Hz, 1H); 6.51 (s, 1H); 3.94 (d, J = 2.03 Hz, 2H);3.87 (s, 3H); 2.44 (s, 3H).2-(6-chloro-2-fluoro-3-methoxyphenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2- yl)phenyl)acetamide (Off-whitesolid) 68

3.38^(a) (99.1%) 399 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.64 (s,1H); 8.02- 7.98 (m, 2H); 7.87-7.81 (m, 2H); 7.17-7.08 (m, 2H); 6.50 (s,1H); 3.92 (s, 4H); 3.80 (s, 3H); 2.44 (s, 3H).2-(2,4-difluoro-3-methoxyphenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 67

4.03^(a) (95.7%) 469 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.85 (s,1H); 8.04- 7.96 (m, 4H); 7.86-7.78 (m, 2H); 6.50 (s, 1H); 4.21 (s, 2H);2.44 (s, 3H).2-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 66

3.88^(a) (98.7%) 419 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.66 (s,1H); 8.03- 7.97 (m, 2H); 7.84-7.77 (m, 3H); 7.46 (dd, J = 9.81, 2.65 Hz,1H); 7.40-7.33 (m, 1H); 6.50 (s, 1H); 4.03 (s, 2H); 2.44 (s, 3H).2-(5-fluoro-2-(trifluoromethyl)phenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (White solid) 65

2.86^(b) (99.2%) 385 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.66 (s,1H); 8.03- 7.97 (m, 2H); 7.87-7.81 (m, 2H); 7.53-7.43 (m, 2H); 7.23 (td,J = 8.52, 2.71 Hz, 1H); 6.52 (s, 1H); 3.91 (s, 2H); 2.45 (s, 3H).2-(2-chloro-4-fluorophenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 64

3.33^(a) (99.4%) 358 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.65 (s,1H); 8.02- 7.98 (m, 2H); 7.89-7.79 (m, 3H); 7.76 (dt, J = 7.69, 1.44 Hz,1H); 7.70 (d, J = 7.90 Hz, 1H); 7.57 (t, J = 7.73 Hz, 1H); 6.50 (s, 1H);3.83 (s, 2H); 2.44 (s, 3H). 2-(3-cyanophenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 63

10.0^(c)  (97.9%) 367 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.61 (s,1H); 8.03- 7.96 (m, 2H); 7.87-7.80 (m, 2H); 7.43 (s, 1H); 7.41-7.29 (m,3H); 6.51 (s, 1H); 3.75 (s, 2H); 2.44 (s, 3H).2-(3-chlorophenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 62

3.01^(b) (98.8%) 401 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.67 (s,1H); 8.04- 7.98 (m, 2H); 7.87-7.81 (m, 2H); 7.63 (d, J = 2.12 Hz, 1H);7.49 (d, J = 8.29 Hz, 1H); 7.44 (dd, J = 8.25, 2.14 Hz, 1H); 6.50 (s,1H); 3.92 (s, 2H); 2.44 (s, 3H).2-(2,4-dichlorophenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)acetamide (Off-white solid) 61

3.75^(a) (98.3%) 387 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.70 (s,1H); 8.05- 7.97 (m, 2H); 7.87-7.79 (m, 2H); 7.51-7.42 (m, 1H); 7.22-7.17(m, 1H); 6.50 (s, 1H); 3.90 (s, 2H); 2.44 (s, 3H).N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(2,3,5-trifluorophenyl)acetamide (White solid) 60

2.31^(b) (99.5%) 347 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.58 (s,1H); 8.04- 7.96 (m, 2H); 7.89-7.83 (m, 2H); 7.28-7.22 (m, 1H); 7.21-7.12(m, 3H); 6.50 (s, 1H); 3.75 (s, 2H); 2.44 (s, 3H); 2.30 (s, 3H).N-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-2-o-tolyl-acetamide (Off-white solid) 57

2.74^(b) (99.3%) 389 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.57 (s,1H); 8.01- 7.96 (m, 2H); 7.88-7.82 (m, 2H); 7.38-7.33 (m, 2H); 7.27 (d,J = 8.16 Hz, 2H); 6.50 (s, 1H); 3.66 (s, 2H); 2.44 (s, 3H); 1.27 (s, 9H). 2-(4-tert-Butyl-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide (Off-white solid) 56

3.15^(b) (91.2%) 409 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.69 (s,1H); 8.00 (d, J = 8.48 Hz, 2H); 7.87 (d, J = 8.53 Hz, 2H); 7.65 (t, J =7.91 Hz, 4H); 7.50-7.42 (m, 4H); 7.36 (t, J = 7.42 Hz, 1H); 6.50 (s,1H); 3.76 (s, 3H); 2.44 (s, 4H).2-Biphenyl-4-yl-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide (Off-white solid) 55

2.73^(b) (98.9) 415 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): 10.57 (1H, s),8.01-7.95 (2H, m), 7.87-7.81 (2H, m), 7.77-7.66 (2H, m), 7.67-7.56 (2H,m), 6.49 (1H, s), 4.02 (1H, q, J = 6.99 Hz), 2.44 (3H, s), 1.49 (3H, d,J = 6.97 Hz). N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)propanamide (Off-white solid) 53

3.10^(a) (98.3%) 363 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.50 (s,1H); 8.01- 7.96 (m, 2H); 7.89-7.82 (m, 2H); 7.28-7.21 (m, 2H); 6.99 (d,J = 8.16 Hz, 1H); 6.92 (td, J = 7.41, 1.12 Hz, 1H); 6.50 (s, 1H); 3.77(s, 3H); 3.70 (s, 2H); 2.44 (s, 2H).2-(2-Methoxy-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide (White solid) 51

2.49^(b) (98.9%) 361 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.59 (s,1H); 8.02 (d, J = 8.63 Hz, 2H); 7.87 (d, J = 8.65 Hz, 2H); 6.95 (s, 2H);6.89 (s, 1H); 6.72 (s, 1H); 3.62 (s, 2H); 2.26 (s, 6H).2-(3,5-Dimethyl-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide (White solid) 50

2.95^(b) (99.2%) 361 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.58 (s,1H); 8.03- 7.96 (m, 2H); 7.90-7.82 (m, 2H); 7.06 (d, J = 5.91 Hz, 2H);7.00-6.94 (m, 1H); 6.55 (s, 1H); 3.71 (s, 2H); 2.25 (s, 6H).2-(2,5-Dimethyl-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide (White solid) 49

9.58^(c) (97.2%) 358 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.67 (s,1H); 8.04- 7.96 (m, 2H); 7.87-7.79 (m, 4H); 7.55 (d, J = 8.06 Hz, 2H);6.50 (s, 1H); 3.86 (s, 2H); 2.44 (s, 3H).2-(4-Cyano-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide (Off-white solid) 48

3.9^(a)  (96.9%) 401 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.66 (s,1H); 8.02- 7.97 (m, 2H); 7.87-7.81 (m, 2H); 7.72 (d, J = 8.06 Hz, 2H);7.58 (d, J = 8.01 Hz, 2H); 6.50 (s, 1H); 3.85 (s, 2H); 2.44 (s, 3H).N-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide (Off-white solid) 47

3.8^(a)  (98.25%) 367 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.60 (s,1H); 8.04- 7.96 (m, 2H); 7.88-7.80 (m, 2H); 7.43-7.35 (m, 4H); 6.50 (s,1H); 3.73 (s, 2H); 2.44 (s, 3H).2-(4-Chloro-phenyl)-N-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-acetamide (Off-white solid) ^(a-f)Rtrefers to HPLC methods A to F

Representative Method G

A carousel tube was charged with a solution of Intermediate 4 (0.23mmol) in dichloromethane (4 mL) and the appropriate isocyanate (0.27mmol) was added. After 18 hours at 60° C., the reaction mixture wasconcentrated in vacuo and purified by preparative HPLC.

The following compounds were prepared using representative method G withintermediate 4 and an appropriate isocyanate:

Ex HPLC Rt No Structure (Appareance) (% Purity) MS NMR 52

3.00^(b) (98.9%) 402 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d⁶): δ 9.32 (s, 1H);9.22 (s, 1H); 8.04 (s, 1H); 7.98 (d, J = 8.51 Hz, 2H); 7.73 (d, J = 8.52Hz, 2H); 7.61 (d, J = 8.29 Hz, 1H); 7.54 (t, J = 7.88 Hz, 1H); 7.36 (d,J = 7.58 Hz, 1H); 6.50 (s, 1H); 2.45 (s, 3H).1-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (Yellow solid) 54

2.74^(b) (94.1%) 382 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.22 (s,1H); 7.92 (d, J = 8.53 Hz, 2H); 7.65 (d, J = 8.55 Hz, 2H); 7.44 (dd, J =17.20, 7.56 Hz, 2H); 7.39-7.27 (m, 2H); 6.89 (t, J = 6.05 Hz, 1H); 6.48(s, 1H); 4.40 (d, J = 5.90 Hz, 2H); 2.43 (s, 3H).1-(2-Chloro-benzyl)-3-[4-(5-methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-urea (Orange solid) 58

2.88^(b) (97.4%) 402 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d⁶): δ 7.98 (d, J =8.66 Hz, 2H); 7.93 (d, J = 8.31 Hz, 1H); 7.74-7.68 (m, 3H); 7.66 (t, J =8.05 Hz, 1H); 7.36-7.28 (m, 1H); 6.50 (s, 1H); 2.44 (s, 3H).1-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-3-(2-trifluoromethyl-phenyl)-urea (Orange solid) 59

3.08^(b) (98.7%) 418 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.60 (s,1H); 9.41 (s, 1H); 8.01- 7.93 (m, 2H); 7.77-7.69 (m, 2H); 7.63-7.58 (m,2H); 7.31 (d, J = 8.61 Hz, 2H); 6.50 (s, 1H); 2.45 (s, 3H).1-[4-(5-Methyl-imidazo[5,1-b][1,2,4]oxadiazol-2-yl)-phenyl]-3-(4-trifluoromethoxy-phenyl)-urea (Orange solid) ^(a-f)Rtrefers to HPLC methods A to F

Representative Method H Step 1:

To a suspension of amine (3.35 mmol) in EtOH (5 mL) was added2,4-dichloropyrimidine (500 mg, 3.35 mmol) and DIPEA (0.58 mL, 3.35mmol). The reaction mixture was sonicated for 30 seconds then stirred at25° C. After 16 hours the reaction mixture was concentrated underreduced pressure onto silica gel. The crude product was purified bychromatography (silica gel, isohexane/ethyl acetate) to afford the 2-and 4-substituted aminopyrimidine products. As Examples:N-benzyl-4-chloropyrimidin-2-amine ¹H NMR (400 MHz, DMSO-d⁶): δ8.26-8.18 (m, 2H); 7.35-7.28 (m, 4H); 7.25-7.20 (m, 1H); 6.69 (d, J=5.15Hz, 1H); 4.49 (s, 2H).2-chloro-N-(2-(trifluoromethyl)benzyl)pyrimidin-4-amine ¹H NMR (400 MHz,DMSO-d⁶): δ 8.43 (s, 1H); 7.99 (d, J=6.04 Hz, 1H); 7.76 (d, J=7.82 Hz,1H); 7.68 (t, J=7.65 Hz, 1H); 7.56-7.47 (m, 2H); 6.60 (d, J=5.98 Hz,1H); 4.69 (s, 2H).

Step 2:

A carousel tube was charged with a suspension of chloropyrimidine amine(0.45 mmol) in DMF (1 mL) and a solution of Intermediate 4 (0.45 mmol)in DMF (1 mL). The reaction was gently heated until a solution formed,then p-toluenesulfonic acid (172 mg, 0.9 mmol) was added, the reactiontube was sealed and heated at 60° C. After 11 hours the reaction wascooled to 25° C. then cautiously diluted with saturated Na₂CO₃ aqueoussolution. The reaction was extracted using EtOAc, the organic phaseswere combined and concentrated under reduced pressure. The crude productwas dissolved in DMF and purified by preparative HPLC.

The following compounds were prepared using representative method H withintermediate 4 and an appropriate chloropyrimidine:

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 72

2.27^(b) (91.4%) 398 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.67 (s, 1H); 7.96 (d, J = 5.63 Hz, 1 H); 7.86 (s, 4 H); 7.56 (s, 1 H); 7.39-7.29(m, 4 H); 7.22 (t, J = 7.11 Hz, 1 H); 6.53-6.47 (m, 1 H); 6.10 (d, J =5.65 Hz, 1 H); 4.52 (d, J = 6.26 Hz, 2 H); 2.45 (s, 3 H). 74

7.06^(d) (93.9%) 466 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.61 (s, 1H); 7.96 (d, J = 5.78 Hz, 1 H); 7.93-7.68 (m, 5 H); 7.71-7.62 (m, 1 H);7.56 (d, J = 7.86 Hz, 1 H); 6.51-6.47 (m, 1 H); 6.22 (s, 1 H); 4.80 (s,2 H); 2.43 (s, 3 H). 75

6.97^(d) (96.4%) 412 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.58 (s, 1H); 7.98-7.87 (m, 6 H); 7.27-7.12 (m, 3 H); 7.07 (d, J = 7.49 Hz, 1 H);6.48 (s, 1 H); 6.12 (s, 1 H); 4.55 (s, 2 H); 2.44 (s, 3 H); 2.31 (s, 3H). 76

3.36^(a) (94.4%) 466 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.60 (s, 1H); 7.99-7.87 (m, 4 H); 7.84 (d, J = 8.54 Hz, 2 H); 7.73 (s, 1 H); 7.69(d, J = 7.19 Hz, 1 H); 7.65-7.57 (m, 2 H); 6.48 (s, 1 H); 6.15 (d, J =5.96 Hz, 1 H); 4.68 (s, 2 H); 2.44 (s, 3 H). ^(a-f)Rt refers to HPLCmethods A to F

The following compounds were prepared using representative method F withintermediate 5 and an appropriate acid of formula (V):

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 78

3.73^(a) (99.3%) 426 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.83 (s, 1H); 8.95 (d, J = 2.45 Hz, 1 H); 8.35 (dd, J = 8.71, 2.49 Hz, 1 H); 8.16(d, J = 8.69 Hz, 1 H); 7.43-7.35 (m, 4 H); 7.17-7.11 (m, 1 H); 7.02-6.97(m, 4 H); 6.53 (s, 1 H); 3.75 (s, 2 H); 2.46 (s, 3 H). 79

2.63^(b) (97.8%) 370 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.92 (s, 1H); 8.94 (d, J = 2.48 Hz, 1 H); 8.32 (dd, J = 8.70, 2.51 Hz, 1 H); 8.16(d, J = 8.69 Hz, 1 H); 7.41-7.33 (m, 1 H); 7.28-7.16 (m, 2 H); 6.53 (s,1 H); 3.93 (s, 2 H); 2.46 (s, 3 H). 80

3.75^(a) (98.3%) 410 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 11.06 (s, 1H); 8.95 (d, J = 2.46 Hz, 1 H); 8.38 (dd, J = 8.71, 2.50 Hz, 1 H); 8.15(d, J = 8.70 Hz, 1 H); 7.40-7.24 (m, 10 H); 6.53 (s, 1 H); 5.26 (s, 1H); 2.46 (s, 3 H). 81

2.78^(b) (99.4%) 418 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.89 (s, 1H); 8.93 (d, J = 2.45 Hz, 1 H); 8.32 (dd, J = 8.70, 2.48 Hz, 1 H); 8.16(d, J = 8.69 Hz, 1 H); 7.54-7.49 (m, 1 H); 7.48-7.36 (m, 3 H); 6.53 (s,1 H); 3.90 (s, 2 H); 2.46 (s, 3 H). 82

2.85^(b) (98.9%) 402 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.89 (s, 1H); 8.93 (d, J = 2.45 Hz, 1 H); 8.32 (dd, J = 8.70, 2.48 Hz, 1 H); 8.16(d, J = 8.69 Hz, 1 H); 7.54-7.49 (m, 1 H); 7.48-7.36 (m, 2 H); 6.53 (s,1 H); 3.90 (s, 2 H); 2.46 (s, 3 H). 83

3.45^(a) (99.6%) 402 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.88 (s, 1H); 8.94 (d, J = 2.45 Hz, 1 H); 8.30 (dd, J = 8.71, 2.49 Hz, 1 H); 8.16(d, J = 8.69 Hz, 1 H); 7.74 (d, J = 7.87 Hz, 1 H); 7.68 (t, J = 7.60 Hz,1 H); 7.59-7.49 (m, 2 H); 6.53 (s, 1 H); 4.04 (s, 2 H); 2.46 (s, 3 H).84

10.2^(c) (96.3%) 408 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.07 (s, 1H); 8.97 (d, J = 2.44 Hz, 1 H); 8.36 (dd, J = 8.73, 2.49 Hz, 1 H); 8.13(d, J = 8.73 Hz, 1 H); 7.53-7.41 (m, 4 H); 6.52 (s, 1 H); 2.88 (dt, J =11.49, 7.70 Hz, 2 H); 2.57-2.42 (m, 2 H); 2.45 (s, 3 H); 1.93-1.80 (m, 2H). 85

3.17^(a) (99.0)% 362 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.74 (s, 1H); 8.92 (d, J = 2.48 Hz, 1 H); 8.36 (dd, J = 8.71, 2.51 Hz, 1 H); 8.14(d, J = 8.70 Hz, 1 H); 7.44-7.37 (m, 2 H); 7.36 (t, J = 7.50 Hz, 2 H);7.29-7.24 (m, 1 H); 6.52 (s, 1 H); 3.65 (t, J = 7.55 Hz, 1 H); 2.12-2.06(m, 1 H); 1.79-1.73 (m, 1 H); 0.88 (t, J = 7.29 Hz, 3 H). ^(a-f)Rtrefers to HPLC methods A to F

Representative Method I

To a suspension of bis(trimethylaluminum)-1,4-diazabicyclo(2.2.2)octaneadduct (DABAL-Me₃, 115 mg, 0.45 mmol) in THF (3 mL) in a carousel tube,was added an appropriate amine of formula (III) (0.45 mmol), thereaction was heated at 40° C. for 45 minutes. Ester derivative (0.3mmol) was added and the reaction was flushed with nitrogen, sealed andheated to 70° C. After 16 hours the reaction was cooled to 25° C.,quenched with dilute aqueous HCl solution (2 mL) and then stirred for 20minutes. The organic phase was collected and the aqueous phase wasextracted with EtOAc. The organic fractions were dried (MgSO₄), filteredover silica and concentrated under reduced pressure. The residue wasdissolved in DMSO and purified by reverse phase preparative HPLC.

The following compounds were prepared using representative method I withintermediate 6 and an appropriate amine of formula (III).

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 86

3.72^(a) (97.3%) 383 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.33 (t, J =5.70 Hz, 1 H); 8.22-8.10 (m, 5 H); 8.00- 7.94 (m, 1 H); 7.88 (d, J =7.70 Hz, 1 H); 7.64-7.48 (m, 4 H); 6.55 (s, 1 H); 4.99 (d, J = 5.64 Hz,2 H); 2.47 (s, 3 H). 87

3.02^(b) (97.3%) 401 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.35 (t, J =5.74 Hz, 1 H); 8.22-8.10 (m, 4 H); 7.62- 7.56 (m, 1 H); 7.40-7.34 (m, 2H); 6.56 (s, 1 H); 4.61 (d, J = 5.68 Hz, 2 H); 2.48 (s, 3 H). 88

8.25^(d) (94.7%) 423 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.34 (t, J =5.80 Hz, 1 H); 8.18-8.01 (m, 6 H); 7.75 (s, 1 H); 7.42 (dd, J = 8.57,2.10 Hz, 1 H); 6.55 (s, 1 H); 4.73 (d, J = 5.74 Hz, 2 H); 2.47 (s, 3 H).^(a-f)Rt refers to HPLC methods A to F

The following compounds were prepared using representative method E withintermediate 10 and an appropriate amine of formula (III).

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 29

2.98^(b) (97.9%) 405 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.27 (s, 1H); 7.85 (d, J = 8.74 Hz, 2 H); 7.78 (d, J = 2.31 Hz, 1 H); 7.50-7.39(m, 4 H); 7.28 (d, J = 8.28 Hz, 2 H); 6.46 (s, 1 H); 5.97 (d, J = 2.31Hz, 1 H); 5.27 (s, 2 H); 2.43 (s, 3 H). 30

3.13^(b) (98.5%) 439 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.29 (s, 1H); 7.87-7.78 (m, 3 H); 7.67-7.60 (m, 1 H); 7.55-7.44 (m, 3 H); 7.24(dd, J = 8.30, 2.08 Hz, 1 H); 6.46 (s, 1 H); 5.99 (d, J = 2.33 Hz, 1 H);5.29 (s, 2 H); 2.43 (s, 3 H). ^(a-f)Rt refers to HPLC methods A to F

Representative Method J

An appropriate amine of formula (III) (0.4 mmol) was dissolved in DCM (3mL) and diisopropylethylamine (0.174 mL, 1 mmol). Intermediate 12,hydrochloride salt (80 mg, 0.36 mmol) was added and the reaction wasleft to stir for approximately 15 minutes until all the reagents were insolution. HATU (152 mg, 0.4 mmol) was added and the reaction was left tostir at 25° C. for 6 h. The DCM solution was then extracted withsaturated aqueous sodium bicarbonate solution, dried (MgSO₄), filteredand concentrated in vacuo. The crude residue was then purified byreverse-phase preparative HPLC.

The following compounds were prepared using representative method J withintermediate 12 and an appropriate amine of formula (III):

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 105

3.07^(b) (98.8%) 323 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃- d): δ 8.06 (d, J =8.28 Hz, 1 H); 7.95-7.86 (m, 2 H); 7.63-7.53 (m, 3 H); 7.53-7.47 (m, 1H); 7.17 (s, 1 H); 6.96 (s, 1 H); 5.13 (d, J = 5.65 Hz, 2 H); 2.59 (s, 3H). 106

3.37^(b) (98.7%) 383 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.78 (t, J =6.21 Hz, 1 H); 7.35 (d, J = 8.41 Hz, 2 H); 7.23- 7.16 (m, 2 H);7.07-6.93 (m, 4 H); 4.43 (d, J = 6.21 Hz, 2 H); 2.59 (s, 3 H). 107

3.39^(a) (96.3%) 365 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.77 (t, J =6.20 Hz, 1 H); 7.37 (t, J = 8.11 Hz, 4 H); 7.13- 7.08 (m, 1 H);7.01-6.95 (m, 5 H); 4.44 (d, J = 6.21 Hz, 2 H); 2.58 (s, 3 H). 108

3.39^(a) (99.7%) 327 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 7.42 (t, J =7.54 Hz, 2 H); 7.36-7.25 (m, 3 H); 7.00 (d, J = 19.64 Hz, 1 H); 6.05 (s,0.39 H); 5.81 (s, 0.61 H); 4.67 (d, J = 13.67 Hz, 0.61 H); 4.42 (s, 0.39H); 3.27-3.00 (m, 1 H); 2.81 (s, 1 H); 2.70-2.30 (m, 3 H); 2.18- 1.86(m, 2 H); 1.84-1.34 (m, 3 H). 109

3.35^(a) (97.2%) 345 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 8.19 (s, 1H); 7.43 (dd, J = 8.36, 5.51 Hz, 2 H); 7.23 (td, J = 8.77, 2.72 Hz, 2H); 7.01 (d, J = 7.38 Hz, 1 H); 4.85 (d, J = 13.18 Hz, 0.5 H); 4.51 (dd,J = 26.74, 12.52 Hz, 0.5 H); 3.11-2.96 (m, 2 H); 2.63 (s, 0.5 H);2.57-2.54 (m, 2, 5H); 2.04-1.85 (m, 3 H). 110

3.25^(b) (99.8%) 391 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 7.56-7.46(m, 2 H); 7.23 (dd, J = 12.02, 8.33 Hz, 2 H); 7.07 (s, 0.58 H); 6.95 (s,0.42 H); 5.87 (d, J = 7.93 Hz, 0.42 H); 5.21 (dd, J = 7.89, 4.46 Hz,0.58 H); 4.34-4.16 (m, 1 H); 3.97-3.89 (m, 0.42 H); 3.82-3.71 (m, 0.58H); 2.65 (s, 1.74 H); 2.55-2.22 (m, 1.76 H); 2.04-1.74 (m, 2.5 H). 111

2.79^(a) (94.4%) 349 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.65 (t, J =6.00 Hz, 1 H); 7.47-7.30 (m, 8 H); 7.22 (dd, J = 7.16, 1.85 Hz, 1 H);6.96 (s, 1 H); 4.42 (d, J = 5.97 Hz, 2 H); 2.58 (s, 3 H). 112

8.53^(d) (98.5%) 381 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.61 (dd, J =8.02, 4.65 Hz, 2 H); 7.34 (dd, J = 21.64, 8.06 Hz, 2 H); 6.97 (s, 0.54H); 6.90-6.85 (m, 0.46 H); 6.04 (d, J = 8.04 Hz, 0.46 H); 5.41 (dd, J =8.06, 4.36 Hz, 0.54 H); 4.46-4.29 (m, 1 H); 4.11-4.03 (m, 0.5 H); 3.95(ddd, J = 12.90, 9.86, 7.30 Hz, 0.5 H); 2.73 (s, 1.62 H); 2.60-2.41 (m,0.5 H); 2.40 (s, 1.38 H); 2.26-1.93 (m, 2.5 H). Restricted rotation 113

3.80^(a) (99.7%) 391 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.44 (t, J =8.75 Hz, 2 H); 7.12 (d, J = 8.16 Hz, 1 H); 7.04 (d, J = 8.14 Hz, 1 H);6.94 (s, 0.5 H); 6.85 (s, 0.5 H); 5.93 (d, J = 7.84 Hz, 0.5 H); 5.30(dd, J = 7.93, 4.30 Hz, 0.5 H); 4.38-4.25 (m, 1 H); 4.06-3.98 (m, 0.5H); 3.93-3.86 (m, 0.5 H); 2.71 (s, 1.5 H); 2.54-2.30 (m, 2 H); 2.18-1.89(m, 2.5 H). Presence of rotamers 114

3.82^(a) (99.7%) 391 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.44 (t, J =8.75 Hz, 2 H); 7.12 (d, J = 8.16 Hz, 1 H); 7.04 (d, J = 8.14 Hz, 1 H);6.94 (s, 0.5 H); 6.85 (s, 0.5 H); 5.93 (d, J = 7.84 Hz, 0.5 H); 5.30(dd, J = 7.93, 4.30 Hz, 0.5 H); 4.38-4.25 (m, 1 H); 4.06-3.98 (m, 0.5H); 3.93-3.86 (m, 0.5 H); 2.71 (s, 1.5 H); 2.54-2.30 (m, 2 H); 2.18-1.89(m, 2.5 H). Presence of rotamers 115

3.66^(a) (98.3%) 361 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 7.50-7.40(m, 2 H); 7.36- 7.25 (m, 2 H); 6.88 (s, 1 H); 6.10 (s, 0.5 H); 5.63-5.53(m, 0.5 H); 4.74 (s, 0.5 H); 4.53 (s, 0.5 H); 3.75 (s, 1 H); 2.39 (s, 2H); 2.10 (s, 1 H); 1.99-1.42 (m, 5 H); 116

3.65^(a) (99.0%) 395 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 7.65 (s, 4H); 6.97 (s, 0.5 H); 6.51 (s, 0.5 H); 6.05 (s, 0.5 H); 5.82 (s, 0.5 H);4.68 (s, 0.5 H); 4.43 (s, 0.5 H); 3.10 (s, 0.5 H); 2.81 (s, 0.5 H); 2.57(s, 2 H); 2.32 (s, 1 H); 1.99 (s, 1 H); 1.83-1.27 (m, 4 H). 117

3.12^(b) (98.9%) 341 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 7.39-7.09(m, 5 H); 6.90 (d, J = 9.28 Hz, 1 H); 5.20 (s, 0.63 H); 4.84 (s, 0.37H); 4.48 (d, J = 13.64 Hz, 0.37 H); 4.35 (d, J = 13.42 Hz, 0.63 H); 3.17(d, J = 18.18 Hz, 2 H); 2.97 (dd, J = 13.35, 7.55 Hz, 1H); 2.57 (s, 2H); 2.53 (s, 1 H); 1.90-1.39 (m, 5 H). 118

3.13^(b) (99.9%) 347 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.34-7.22 (m,2 H); 7.17 (d, J = 8.27 Hz, 1 H); 7.10 (d, J = 8.24 Hz, 1 H); 6.94 (s,0.5H H); 6.85 (s, 0.5 H); 5.95 (d, J = 7.81 Hz, 0.5 H); 5.32 (dd, J =7.93, 4.29 Hz, 0.5 H); 4.41-4.25 (m, 0.5 H); 4.06- 3.98 (m, 0.5 H);3.94-3.85 (m, 0.5 H); 2.71 (s, 1.5 H); 2.54-2.29 (m, 2 H); 2.20-1.89 (m,2.5 H). Restricted rotation 119

3.08^(a) (98.1%) 327 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.19-6.99 (m,4 H); 6.93 (s, 0.5 H); 6.88-6.80 (m, 0.5 H); 5.95 (d, J = 7.89 Hz, 0.5H); 5.33 (dd, J = 7.91, 4.10 Hz, 0.5 H); 4.40-4.23 (m, 0.5 H); 4.07-3.99(m, 0.5 H); 3.93-3.83 (m, 0.5 H); 2.71 (s, 1.5 H); 2.47 (s, 1.5 H);2.52-2.28 (m, 1.5 H); 2.32 (s, 1.5 H); 2.29 (s, 1.5 H); 2.32- 2.12 (m,0.5 H); 2.11-1.92 (m, 2.5 H). 120

3.82^(a) (99.9%) 327 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): 7.44 (2 H, t, J= 8.75 Hz), 7.12 (1 H, d, J = 8.16 Hz), 7.04 (1 H, d, J = 8.14 Hz), 6.94(0.5 H, s), 6.85 (0.5 H, s), 5.93 (0.5 H, d, J = 7.84 Hz), 5.30 (0.5 H,dd, J = 7.93, 4.30 Hz), 4.38-4.25 (1 H, m), 3.93-3.86 (1 H, m), 2.71(1.5 H, s), 2.54-2.30 (2.5 H, m), 2.18-1.89 (3 H, m). 121

3.00^(b) (97.9%) 327 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.21-7.09 (m,3 H); 7.04 (dd, J = 8.73, 5.04 Hz, 0.32 H); 6.97-6.93 (m, 1 H); 6.84 (s,0.68 H); 6.07 (d, J = 8.01 Hz, 0.68 H); 5.55 (dd, J = 8.05, 3.86 Hz,0.32 H); 4.47 (ddd, J = 11.92, 7.80, 4.83 Hz, 0.32 H); 4.35-4.28 (m,0.32 H); 4.16-4.08 (m, 0.68 H); 3.96-3.86 (m, 0.68 H); 2.72 (s, 1 H);2.50-2.38 (m, 5.5 H); 2.14-1.94 (m, 2.5 H). 122

3.13^(b) (97.9%) 347 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.45-7.39 (m,1 H); 7.32-7.10 (m, 2 H); 7.14-7.10 (m, 0.77 H); 7.09- 7.01 (m, 1 H);6.97 (s, 0.23 H); 6.86 (s, 0.77 H); 6.26 (d, J = 8.06 Hz, 0.77 H); 5.70(dd, J = 8.11, 3.90 Hz, 0.23 H); 4.46 (dd, J = 12.03, 6.13 Hz, 0.23 H);4.33-4.28 (m, 0.23 H); 4.15-4.06 (m, 0.77 H); 3.93 (ddd, J = 12.92,10.29, 7.32 Hz, 0.77 H); 2.72 (s, 0.7H) 2.64- 2.37 (m, 2.8 H); 2.16-1.89(m, 2.5 H). 123

3.43^(a) (97.7%) 391 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.41 (dd, J =7.74, 1.46 Hz, 0.5 H); 7.37 (d, J = 7.16 Hz, 2 H); 7.21 (dt, J = 13.03,7.66 Hz, 2 H); 7.10 (d, J = 7.78 Hz, 0.5 H); 6.97 (s, 0.5 H); 6.87 (s,0.5 H); 5.92 (d, J = 7.92 Hz, 0.5 H); 5.33 (dd, J = 7.92, 4.12 Hz, 0.5H); 4.42-4.36 (m, 0.5 H); 4.35-4.29 (m, 0.5 H); 4.06 (dd, J = 13.22,6.50 Hz, 0.5 H); 3.98-3.90 (m, 0.5 H); 2.73 (s, 1.5 H); 2.56- 2.36 (m, 2H); 2.22-1.94 (m, 2.5 H). 124

7.93^(d) (98.6%) 331 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.27-7.19 (m,1 H); 7.19-7.11 (m, 1 H); 7.09-6.97 (m, 2 H); 6.97 (s, 0.5 H); 6.88 (s,0.5 H); 5.97 (d, J = 7.79 Hz, 0.5 H); 5.36 (dd, J = 7.88, 4.25 Hz, 0.5H); 4.43-4.27 (m, 1 H); 4.08-4.00 (m, 0.5 H); 3.96-3.87 (m, 0.5 H); 2.73(s, 1.5 H); 2.54- 2.31 (m, 2 H); 2.25-1.93 (m, 3 H). ^(a-f)Rt refers toHPLC methods A to F

The following compounds were prepared using representative method F withintermediate 13 and an appropriate carboxylic acid of formula (V).

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 125

3.16^(b) (97.4%) 429 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.77 (s, 1H); 8.12 (t, J = 7.95 Hz, 2 H); 7.98-7.93 (m, 1 H); 7.89-7.84 (m, 1 H);7.74 (d, J = 1.92 Hz, 1 H); 7.62-7.48 (m, 4 H); 7.33 (dd, J = 8.72, 1.93Hz, 1 H); 6.88 (s, 1 H); 4.22 (s, 2 H); 3.94 (s, 3 H); 2.58 (s, 3 H).126

3.18^(b) (96.3%) 407 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.56 (s, 1H); 8.11 (d, J = 8.68 Hz, 1 H); 7.73 (d, J = 1.91 Hz, 1 H); 7.32 (dd, J= 8.71, 1.93 Hz, 1 H); 7.09- 7.05 (m, 2 H); 6.98 (dd, J = 7.67, 1.84 Hz,1 H); 6.89 (s, 1 H); 3.96 (s, 3 H); 3.70 (s, 2 H); 2.63-2.39 (m, 3 H);2.26 (s, 6 H). ^(a-f)Rt refers to HPLC methods A to F

The following compound was prepared using representative method I withintermediate 14 and an appropriate amine of formula (III).

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 127

3.19^(b) (98.7%) 399 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.28 (t, J =5.72 Hz, 1 H); 8.18 (d, J = 8.14 Hz, 1 H); 8.09 (d, J = 8.27 Hz, 2 H);8.02 (d, J = 8.26 Hz, 2 H); 7.97-7.93 (m, 1 H); 7.88-7.83 (m, 1 H);7.61-7.47 (m, 4 H); 6.97 (s, 1 H); 4.97 (d, J = 5.64 Hz, 2 H); 2.60 (s,3 H). ^(a-f)Rt refers to HPLC methods A to F

The following compounds were prepared using representative method F withintermediate 15 and an appropriate carboxylic acid of formula (V):

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 128

3.07^(b) (98.6%) 417 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.58 (s, 1H); 7.90- 7.84 (m, 2 H); 7.82-7.76 (m, 2 H); 7.62-7.57 (m, 2 H); 7.32(dd, J = 8.28, 2.06 Hz, 1 H); 6.93 (s, 1 H); 3.74 (s, 2 H); 2.56 (s, 3H). 100

3.69^(a) (98.5%) 417 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 10.60 (s, 1H); 7.90- 7.84 (m, 2 H); 7.83-7.77 (m, 2 H); 7.70 (s, 1 H); 7.65-7.60(m, 2 H); 7.60-7.53 (m, 1 H); 6.93 (s, 1 H); 3.83 (s, 2 H); 2.56 (s, 3H). ^(a-f)Rt refers to HPLC methods A to F

Representative Method K Step 1:2-(4-isothiocyanatophenyl)-5-methylimidazo[5,1-b][1,3,4]oxadiazole

To a suspension of4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)aniline (1 g, 4.67 mmol)in DCM (50 mL) was added thiocarbonyl pyridine (1.05 g, 4.54 mmol).After 18 hours at 25° C. the reaction mixture was concentrated underreduced pressure to afford the title compound. No further purificationwas carried out. LC-MS 257 (M+H)⁺.

Step 2:1-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)thiourea

2-(4-isothiocyanatophenyl)-5-methylimidazo[5,1-b][1,3,4]oxadiazole(assumed 4.67 mmol) was cooled to 0° C., ammonia in MeOH (2.0 M, 25 mL)was added to the reaction and stirring was continued for 1 hour. Theresulting precipitate was collected by filtration and washed with MeOHto afford the title compound as a yellow solid (1.13 g, 4.15 mmol, 89%yield). LC-MS 274 (M+H)+. ¹H NMR (400 MHz, DMSO-d⁶): δ 10.10 (s, 1H);7.97 (d, J=8.44 Hz, 2H); 7.80 (d, J=8.44 Hz, 2H); 6.51 (s, 1H); 2.45 (s,3H).

Step 3: methyl(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)carbamimidothioatehydroiodide

To a suspension of1-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)thiourea (1.13g, 4.15 mmol) in EtOH (32 mL) was added iodomethane (0.26 mL, 4.15mmol). After 2 hours at 60° C. the reaction was concentrated underreduced pressure to afford the title compound as an orange solid (1.68g, assume 4.15 mmol, 100% yield). LC-MS 288 (M+H)⁺.

Step 4: 5-chloro-2-(4-fluorophenyl)pentanoic acid

To a solution of 2-(4-fluorophenyl)acetic acid (1.54 g, 10 mmol) inanhydrous THF (20 mL) under nitrogen and cooled to 0° C. was addedNaHMDS (1.0M, 20 mL, 20 mmol) dropwise. After 20 minutes at 0° C.1-chloro-3-iodopropane (1.05 mL, 10 mmol) was added and the reaction wasallowed to warm to 25° C. After 16 hours, water (4 mL) was added to thereaction dropwise, which was then concentrated under reduced pressure.The residue was diluted with aqueous NaOH solution (1.0 M) and extractedwith Et₂O. The aqueous phase was acidified with dilute aqueous HClsolution to pH 5 then extracted with Et₂O. The organic phase was washedwith sodium sulfite solution and brine, dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by chromatography(silica, petroleum ether/EtOAc) to afford the title compound as a solid(1.36 g, 5.91 mmol, 59% yield) LC-MS 229 (M−H)−. ¹H NMR (400 MHz,DMSO-d⁶): δ 12.38 (s, 1H); 7.27 (t, J=6.72 Hz, 2H); 7.09 (t, J=8.62 Hz,2H); 3.59-3.48 (m, 3H); 2.03-1.91 (m, 1H); 1.76-1.43 (m, 3H).

Step 5: (Z)-methylN′-(5-chloro-2-(4-fluorophenyl)pentanoyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)carbamimidothioate

To a suspension of 5-chloro-2-(4-fluorophenyl)pentanoic acid (0.26 g,1.14 mmol), methyl(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)carbamimidothioatehydroiodide (0.43 g, 1.04 mmol), EDCI (0.4 g, 2.08 mmol) and HOPO (0.23g, 2.08 mmol) in DMF (5 mL) under N₂ was added DIPEA (0.45 mL, 2.6mmol). After 16 hours the reaction was diluted with water and extractedusing EtOAc. The organic phase was washed with brine, dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified bychromatography (silica gel, EtOAc) to afford the title compound as asolid (0.29 g, 0.58 mmol, 56% yield). LC-MS 500 (M+H)⁺.

Step 6:5-(4-chloro-1-(4-fluorophenyl)butyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-1H-1,2,4-triazol-3-amine

To a suspension of (Z)-methylN′-(5-chloro-2-(4-fluorophenyl)pentanoyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)carbamimidothioate(0.29 g, 0.58 mmol) in EtOH (8 mL) was added hydrazine hydrate (55%aqueous solution, 0.2 mL, 2.32 mmol). After 1 hour at 70° C. thereaction was cooled to 25° C. and degassed with nitrogen for 30 minutes.The reaction was diluted with water and extracted using EtOAc. Theorganic phase was washed with water then brine, dried (MgSO₄) andconcentrated under reduced pressure to afford the title compound as ayellow solid (0.17 g, 0.37 mmol, 64% yield). This was progressed withoutfurther purification. LC-MS 466 (M+H)+. ¹H NMR (400 MHz, DMSO-d⁶): δ13.26 (s, 1H); 9.90 (s, 1H); 7.90 (d, J=8.50 Hz, 2H); 7.74-7.66 (m, 2H);7.42 (dd, J=8.37, 5.40 Hz, 2H); 7.18 (t, J=8.79 Hz, 2H); 6.47 (s, 1H);4.17 (d, J=8.84 Hz, 1H); 3.66 (t, J=6.52 Hz, 2H); 2.43 (s, 3H);2.28-2.17 (m, 1H); 2.21-1.92 (m, 1H); 1.75-1.61 (m, 2H).

Step 7:8-(4-fluorophenyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To a suspension of5-(4-chloro-1-(4-fluorophenyl)butyl)-N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-1H-1,2,4-triazol-3-amine(0.17 g, 0.37 mmol) in acetone (3.5 mL) was added NaI (0.28 g, 1.85mmol), followed by DIPEA (0.065 mL, 0.37 mmol). After 48 hours at 80° C.the reaction was concentrated under reduced pressure. The residue wasdiluted with water and EtOAc. The water was decanted off and resultingsuspension was concentrated under reduced pressure. The residue wasdissolved in DMSO and purified by preparative HPLC. The resultant solidwas triturated with EtOH to afford the title compound as a yellow solid.

The following compounds were prepared using representative method K andintermediate 4.

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 24

9.58^(e) (98.2%) 430 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.86 (s, 1H); 7.85 (d, J = 8.74 Hz, 2 H); 7.62 (d, J = 8.70 Hz, 2 H); 7.30-7.22(m, 2 H); 7.16-7.06 (m, 2 H); 6.42 (s, 1 H); 4.23 (dd, J = 8.97, 5.60Hz, 1 H); 4.14 (t, J = 5.75 Hz, 2 H); 2.39 (s, 3 H); 2.23-2.15 (m, 1 H);2.10-1.88 (m, 3 H). 25

3.19^(b) (99.6%) 480 (M + H)⁺ ¹H NMR (400 MHz, DMSO- d⁶): δ 9.88 (s, 1H); 7.88 (d, J = 8.75 Hz, 2 H); 7.67-7.61 (m, 3 H); 7.39 (dd, J = 8.39,2.23 Hz, 1 H); 7.26 (d, J = 8.39 Hz, 1 H); 6.45 (s, 1 H); 4.57 (dd, J =9.19, 5.84 Hz, 1 H); 4.21-4.10 (m, 2 H); 2.41 (s, 3 H); 2.26-2.17 (m, 1H); 2.11 (s, 3 H). ^(a-f)Rt refers to HPLC methods A to F

Representative Method L Step 1: 2-bromo-6-phenylcyclohexanone

To a solution of phenyl cyclohexanone (2 g, 11.4 mmol) in chloroform (10mL) cooled to −10° C. was added a solution of bromine (1.91 g, 12 mmol)in chloroform dropwise. On completion of the addition the reactionmixture was allowed to warm to 0° C. and stir for 2 h. The solvent wasthen evaporated under reduced pressure, the residue was dissolved inmethanol and cooled to 0° C. and stirred for thirty minutes. The solidobtained was collected by filtration, washed with methanol and dried togive the title compound (255 mg, 1 mmol, 8% yield). ¹H NMR (400 MHz,CHCl₃-d): δ 7.37-7.24 (m, 3H); 7.17-7.12 (m, 2H); 4.80 (ddd, J=13.06,5.96, 1.12 Hz, 1H); 3.71 (dd, J=12.62, 5.32 Hz, 1H); 2.81-2.70 (m, 1H);2.40-2.16 (m, 2H); 2.11-1.88 (m, 3H).

Step 2: 4-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

2-Bromo-6-phenylcyclohexanone (250 mg, 0.98 mmol) and thiourea (75 mg0.98 mmol) in ethanol (10 mL) were heated at reflux for 18 h. Thesolvent was evaporated under reduced pressure. The residue wastriturated with ether to give a solid. The solid was partitioned betweenethyl acetate and aqueous sodium carbonate solution. The ethyl acetateextracts were combined, dried over magnesium sulphate, filtered andevaporated under reduced pressure to give the title compound as a solid(210 mg, 0.91 mmol, 91% yield). LC-MS (M+H)+231. ¹H NMR (400 MHz,CHCl₃-d): δ 7.31-7.25 (m, 3H); 7.21-7.15 (m, 1H); 7.12-7.07 (m, 2H);4.78 (s, 2H); 3.96 (t, J=5.66 Hz, 1H); 2.74-2.58 (m, 2H); 2.19-2.08 (m,1H); 1.91-1.68 (m, 5H).

Step 3:N-(4-(5-methylimidazo[5,1-b][1,3,4]oxadiazol-2-yl)phenyl)-4-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

2-(4-Bromophenyl)-5-methylimidazo[5,1-b][1,3,4]oxadiazole (134.8 mg,0.485 mmol), 4-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (111.5mg, 0.485 mmol), Pd₂dba₃ (17.7 mg, 4 mol %) BINAP (12 mg, 4 mol %) andsodium t-butoxide (65 mg, 0.67) were placed in a carousel tube.1,4-Dioxan was added and the reaction mixture was degassed for a furtherten minutes. The reaction mixture was sealed and heated at 80° C. for 18h. The reaction mixture was poured into aqueous sodium carbonatesolution and extracted with ethyl acetate. The ethyl acetate extractswere combined, washed with brine, dried over magnesium sulphate,filtered and evaporated under reduced pressure to give an oil. The oilwas purified by preparative HPLC to give the title compound (36.4 mg,0.085 mmol, 17.5% yield).

The following compounds were prepared using representative method L andintermediate 4.

HPLC Rt Ex No Structure (Appareance) (% Purity) MS NMR 26

11.43^(c) (97.1%) 428 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.96-7.88(m, 2 H); 7.51 (s, 1 H); 7.37-7.18 (m, 4 H); 7.17-7.11 (m, 2 H); 6.43(s, 1 H); 4.09 (t, J = 5.94 Hz, 1 H); 2.87-2.70 (m, 2 H); 2.54 (s, 3 H);2.28-2.18 (m, 1 H); 1.98-1.78 (m, 2 H). 27

 3.43^(b) (96.9%) 446 (M + H)⁺ ¹H NMR (400 MHz, CHCl₃-d): δ 7.97-7.89(m, 2 H); 7.49 (s, 1 H); 7.39-7.31 (m, 2 H); 7.13-7.07 (m, 2 H);7.03-6.94 (m, 2 H); 6.44 (s, 1 H); 4.07 (t, J = 5.41 Hz, 1 H); 2.83-2.74(m, 2 H); 2.54 (s, 3 H); 2.25-2.17 (m, 1 H); 1.93-1.81 (m, 2 H).^(a-f)Rt refers to HPLC methods A to F

Representative Method E

In an 8 mL vial, a solution of Intermediate 12 (58.6 mg, 0.32 mmol) in 3mL dichloromethane was mixed with amine (III) (0.39 mmol) and Et₃N (1.6mmol). The reaction mixture was then cooled down to 0° C. and T₃P (0.98mmol) was added. After the addition, the vial was placed in the orbitalshaker for about 12 hrs. Upon consumption of starting material(monitored by TLC and LC-MS), reaction mass was concentrated under vacuoto remove the solvent. The crude residue was dissolved indichloromethane (4 mL) and washed with water (2 mL). The organic layerwas evaporated under vacuo and the residue was passed through SPE-NH₂column (2 g, 6 mL) to get the pure amide. The solvents used for elutionwere pet ether/dichloromethane/methanol.

The following compound was prepared from intermediate 12 and anappropriate amine of formula (III):

HPLC Rt Ex No Structure (Appareance) (% Purity) MS  94

2.9^(f)  (98.7%) 326 (M + H)⁺  95

3.26^(f) (99.0%) 321 (M + H)⁺  96

3.17^(f) (98.2%) 317 (M + H)⁺  97

2.92^(f) (99.5%) 301 (M + H)⁺  98

2.8^(f)  (98.5%) 287 (M + H)⁺  99

3.14^(f) (99.6%) 301 (M + H)⁺ 101

3.54^(f) (97.8%) 355 (M + H)⁺ ^(a-f)Rt refers to HPLC methods A to F

Example 89: 5-Methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acidbenzyl-isobutyl-amide

Intermediate 12 (50 mg, 0.23 mmol) was preactivated with HATU (112 mg,0.30 mmol) in a mixture of DCM (4.00 mL) and triethylamine (95.0 μL,0.68 mmol) before adding benzyl-isobutyl-amine (56 mg, 0.34 mmol). Theresulting reaction mixture was stirred at room temperature for 2 hoursand upon completion quenched with water. It was then diluted with DCM(20 mL) and washed with NH₄Cl sat (15 mL) and brine (15 mL). The organicphase was dried with magnesium sulfate and evaporated to yield a crudeproduct purified by flash chromatography (60-120 mesh silica gel,eluent: 50% EtOAc in Petroleum ether) affording the expected compound asa yellow solid (73 mg, 94% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 9.43 (d,J=8.6 Hz, 1H), 7.36 (dd, J=7.6, 1.6 Hz, 1H), 7.32-7.14 (m, 1H),7.09-6.85 (m, 3H), 5.10-5.05 (m, 1H), 4.80-4.78 (m, 1H), 3.85-3.82 (m,2H), 2.63 (s, 3H), 2.10-1.95 (m, 1H), 0.90 (d, J=6.9 Hz, 6H). LC/MS(Method A): 329.4 (M+H)⁺. HPLC (Method F) Rt 3.26 min (Purity. 96.1%).

Example 90: 5-Methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acid[1-(2-ethoxy-phenyl)-ethyl]-amide

The title compound was prepared following the same procedure as Example89, using 1-(2-ethoxy-phenyl)-ethylamine as amine. The resulting crudeproduct was purified by preparative HPLC. The title compound wasobtained as a yellow solid (15 mg, 20% yield). ¹H NMR (DMSO-d₆, 300 MHz)δ 9.43 (d, J=8.6 Hz, 1H), 7.37 (dd, J=7.6, 1.6 Hz, 1H), 7.30-7.17 (m,1H), 7.06-6.86 (m, 3H), 5.52-5.36 (m, 1H), 4.18-4.01 (m, 2H), 2.63 (s,3H), 1.46 (d, J=7.0 Hz, 3H), 1.39 (t, J=6.9 Hz, 3H). LC/MS (Method A):331.3 (M+H)⁺. HPLC (Method F) Rt 3.05 min (Purity: 97.9%).

Example 91: 5-Methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acid[(4-chloro-phenyl)-cyclopropyl-methyl]-amide

Intermediate 12 (50 mg, 0.23 mmol) was preactivated with a T3P solution(80% in EtOAc, 0.27 mL, 0.46 mmol; 2.00 equiv) in a mixture of DCM (4mL) and Hünig's base (0.12 mL, 0.68 mmol) before introducingC-(4-Chloro-phenyl)-C-cyclopropyl-methylamine hydrochloride (59.6 mg,0.27 mmol). The resulting reaction mixture was stirred at roomtemperature for 3 hours and upon completion quenched with water. It wasthen diluted with DCM (20 mL) and washed with NH₄Cl sat (15 mL) andbrine (15 mL). The organic phase was dried with magnesium sulfate andevaporated to yield a crude product purified by preparative HPLCaffording the expected compound as a yellow solid (60 mg, 73% yield). ¹HNMR (DMSO-d₆, 300 MHz) δ 9.93 (d, J=8.2 Hz, 1H), 7.61-7.47 (m, 2H),7.46-7.37 (m, 2H), 6.96 (d, J=7.2 Hz, 1H), 4.31-4.18 (m, 1H), 4.11 (q,J=5.2 Hz, 1H), 3.17 (d, J=5.2 Hz, 1H), 2.62 (d, J=6.7 Hz, 3H), 1.60-1.40(m, 1H), 0.70-0.28 (m, 4H). LC/MS (Method A): 347.3 (M+H)⁺. HPLC (MethodF) Rt 3.29 min (Purity: 97.9%).

Example 92: 5-Methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acid2-(2,2,2-trifluoro-ethoxy)-benzylamide

The title compound was prepared following the same procedure as Example91, using 2-(2,2,2-Trifluoro-ethoxy)-benzylamine as amine. The resultingcrude product was purified by flash chromatography (60-120 mesh silicagel, eluent: 50% EtOAc in Petroleum ether) affording the expectedcompound as a yellow solid (52 mg, 60% yield). ¹H NMR (DMSO-d₆, 300 MHz)δ 9.58 (t, J=6.0 Hz, 1H), 7.34-7.24 (m, 2H), 7.13 (d, J=7.7 Hz, 1H),7.07-7.00 (m, 1H), 6.99 (s, 1H), 4.82 (q, J=8.9 Hz, 2H), 4.49 (d, J=6.0Hz, 2H), 2.60 (s, 3H). LC/MS (Method A): 371.3 (M+H)⁺. HPLC (Method F)Rt 2.95 min (Purity: 97.7).

Example 93:(5-Methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-(2-phenyl-pyrrolidin-1-yl)-methanone

Intermediate 12 (100 mg, 0.46 mmol) was dissolved in a mixture of DCM(10.00 mL) and diisopropylethylamine (309.7 μl, 1.82 mmol) at roomtemperature and preactivated 5 minutes with T3P solution (80% in EtOAc,0.54 mL; 0.91 mmol). 2-Phenyl-pyrrolidine (71 mg, 0.48 mmol) was thenadded and the reaction mixture stirred at 25° C. overnight. The solutionwas quenched with water and the DCM phase washed with a saturated sodiumbicarbonate solution (pH=10) and finally with brine. The organic layerwas dried with magnesium sulphate and concentrated under vacuumaffording an orange residue that was purified on silica gel using 50%EtOAc in pet ether as eluent. The expected compound (140 mg, 98% yield)was obtained as a colorless oil. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.32-7.10(m, 5H), 6.89-6.78 (m, 1H), 5.94 (s, 1H), 4.39-3.79 (brm, 2H), 2.67-1.91(brm, 7H). LC/MS (Method A): 313.3 (M+H)⁺. HPLC (Method F) Rt 2.52 min(Purity: 99.1%).

Example 102:(3,4-Dichloro-benzyl)-[5-(5-methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-[1,3,4]oxadiazol-2-yl]-amine

Step 1: 5-Methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acidhydrazide

Intermediate 11 (200 mg, 0.95 mmol) was heated 1 hour at 60° C. in amixture of hydrazine hydrate solution (24-26% in water, 1.72 mL, 9.5mmol) and THF (5 mL). Upon completion of the reaction, the reactionmixture was evaporated to dryness and the resulting product trituratedwith ethanol, filtered and dried under vacuum affording the titlecompound as a yellow solid (150 mg, 80% yield). LC/MS (Method A): 198.2(M+H)⁺. HPLC (Method F) Rt 3.03 min (Purity: 100%).

Step 2:(3,4-Dichloro-benzyl)-[5-(5-methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-[1,3,4]oxadiazol-2-yl]-amine

A mixture of 5-methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acidhydrazide (75 mg, 0.38 mmol) obtained in Step 1 and1,2-dichloro-4-isocyanatomethyl-benzene (84.5 mg, 0.42 mmol) werestirred 2 hours in THF (50 mL). The resulting yellow precipitateobtained was isolated by filtration and rinsed twice with Et₂O. It wasthen heated in THF (5 mL) at 80° C. for 18 hours in a mixture oftetrachloromethane (0.11 mL, 1.14 mmol), NEt₃ (0.15 mL, 1.14 mmol) andpolymer bound triphenylphosphine (100-200 M, loading=1.6 mmol/g, 398 mg,1.14 mmol). The reaction mixture was cooled down and the resin filteredoff, washed twice with DCM and the organic solvents evaporated todryness. The resulting crude product was purified by flashchromatography on silica gel using EtOAc/MeOH (98/2) as eluent affordingthe title compound as a white solid (160 mg; 91% yield). ¹H NMR(DMSO-d₆, 300 MHz) δ 7.54-7.46 (m, 2H), 7.29-7.25 (m, 1H), 6.99 (s, 1H),5.78-5.70 (m, 1H), 4.66 (d, J=7 Hz, 2H), 2.72 (s, 3H). LC/MS (Method A):382.2 (M+H)⁺. HPLC (Method F) Rt 3.07 min (Purity: 99.3%).

Example 103:(4-Fluoro-benzyl)-[5-(5-methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-[1,3,4]oxadiazol-2-yl]-amine

A mixture of 5-methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acidhydrazide (100 mg, 0.51 mmol), prepared as for Example 102 (Step 1) and1-fluoro-4-isocyanatomethyl-benzene (0.07 mL, 0.56 mmol) were stirred inTHF (50 mL) for 2 hours. The resulting yellow precipitate obtained wasisolated by filtration and rinsed with Et₂O. It was then heated in THF(5 mL) at 80° C. for 18 hours in a mixture of tetrachloromethane (0.11mL, 1.14 mmol), NEt₃ (0.15 mL, 1.14 mmol) and polymer boundtriphenylphosphine (100-200 M, loading=1.6 mmol/g, 398 mg, 1.14 mmol).The reaction mixture was cooled down and the resin filtered off, washedtwice with DCM and the organic solvents evaporated to dryness. Theresulting crude product was purified by flash chromatography on silicagel using EtOAc/MeOH (98/2) as eluent affording the title compound as awhite solid (150 mg, 85% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 7.44-7.37(m, 2H), 7.13-7.05 (m, 2H), 6.95 (s, 1H), 5.95-5.83 (m, 1H), 4.67 (d,J=7 Hz, 2H), 2.72 (s, 3H). LC/MS (Method A): 331.1 (M+H)⁺. HPLC (MethodF) Rt 2.30 min (Purity: 98.2%).

Example 104:(2-Fluoro-benzyl)-[5-(5-methyl-imidazo[5,1-b][1,3,4]thiadiazol-2-yl)-[1,3,4]oxadiazol-2-yl]-amine

A mixture of 5-methyl-imidazo[5,1-b][1,3,4]thiadiazole-2-carboxylic acidhydrazide (100 mg, 0.51 mmol) prepared as for Example 102 (Step 1) and1-fluoro-2-isocyanatomethyl-benzene (0.07 mL, 0.56 mmol) were stirred atRT for 2 hours in THF (50 mL). The resulting yellow precipitate obtainedwas isolated by filtration and rinsed with Et₂O. It was then heated inTHF (5 mL) at 80° C. for 18 hours in a mixture of tetrachloromethane(0.11 mL, 1.14 mmol), NEt₃ (0.15 mL, 1.14 mmol) and polymer boundtriphenylphosphine (100-200 M, loading=1.6 mmol/g, 398 mg, 1.14 mmol).The reaction mixture was cooled down and the resin filtered off, washedtwice with DCM and the organic solvents evaporated to dryness. Theresulting crude product was purified by flash chromatography on silicagel using EtOAc/MeOH (98/2) as eluent affording the title compound as awhite solid (150 mg, 85% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 7.53-7.46(m, 1H), 7.41-7.34 (m, 1H), 7.22-7.11 (m, 2H), 7.05-6.88 (m, 1H),5.67-5.54 (m, 1H), 4.75 (d, J=7 Hz, 2H), 2.74 (s, 3H). LC/MS (Method A):331.1 (M+H)⁺. HPLC (Method F) Rt 2.23 min (Purity: 98.6%).

Example 129: In Vitro Assays Amyloid-β Peptide Release (Aβ42 & AβTotal)Assay to Determine IC₅₀ Values.

Amyloid-β peptide release (Aβ42 & AβTotal) assays are performed in 384well microtiter plates (Perkin Elmer AlphaPlate #6008350) in a finalvolume of 20 μl, using supernatant derived from HEK cells overexpressingAPP (HEK-APP) exposed to test compounds. Compounds are dissolved in anddiluted in 100% DMSO and incubated with HEK-APP cells for 24 h at 37° C.in 5% CO₂. The supernatant from HEK-APP cells are mixed with antibodies:for Aβ42 detection: AlphaLISA Amyloid-ß 1-42 Kit (Perkin Elmer AL203L)Anti-Amyloid ß1-42-specific antibody acceptor beads, biotinylatedanti-Amyloid-“ß1-42” antibody and streptavidin (SA) donor beads dilutedin AlphaLISA buffer (to the instructions of the supplier). For Aβ totaldetection: Custom Anti-Amyloid-βtotal acceptor beads (6E10 acceptorbeads), biotinylated anti-Amyloid “ß1-42” antibody (Perkin Elmer AL203L)and streptavidin (SA) donor beads diluted in AlphaLISA buffer (to theinstructions of the supplier). After addition of supernatant to theantibody mix, the assay is incubated for 4.5 h. Amyloid-β peptiderelease (Aβ42 & AβTotal) is measured with a Pherastar FS (BMG) multimodereader using the alphascreen module.

Cell Viability Assay to Determine IC₅₀ Values.

Cell viability assays are performed in 384 well microtiter plates(Corning #3712) in a final volume of 30 μl, using plates containingHEK-APP cells exposed to test compounds for 24 h. After addition ofequal volume of CellTiter-Glo (Promega) to the cells, the assay isincubated for 10 min. Cell viability is measured with a Pherastar FS(BMG) multimode reader using the Luminescence plus module.

Results are given in the following table:

Ab42 Abtot/Ab42 Ex. IC50 selectivity No Structure Ranges ranges 1

c b 2

d c 3

d c 4

d c 5

c c 6

c c 7

c b 8

d c 9

c c 10

d c 11

b b 12

c c 13

d c 14

d c 15

c b 16

d d 18

d c 19

d c 20

d c 21

d c 22

c c 23

d c 24

c c 25

c c 26

d c 27

d d 28

b d 29

d d 30

d c 31

b a 32

b a 33

c b 34

c b 35

c b 36

d c 37

d c 38

b a 39

c b 40

c b 41

c b 42

c b 43

d c 44

c b 45

c b 46

c b 47

c c 48

d c 49

d c 50

c c 51

c c 52

d d 53

d d 54

d c 55

d c 56

b a 57

c b 58

c d 59

d c 60

d c 61

c b 62

c b 63

c b 64

c b 65

d c 66

d c 67

d c 68

c b 69

c b 70

d c 71

c b 72

d d 73

d c 74

d d 75

d d 76

d d 77

b a 78

d c 79

d c 80

c c 81

d c 82

d c 83

d c 84

c c 85

d c 86

c b 87

d c 88

d c 89

b d 90

c d 91

d d 92

a d 93

b d 94

c d 95

c d 96

c d 97

c d 98

d d 99

d d 100

b b 101

c d 102

b d 103

c d 104

d d 105

c d 106

b b 107

b c 108

c d 109

d d 110

a d 111

d d 112

b d 113

a d 114

d d 115

c d 116

d d 117

d d 118

b d 119

b d 120

c d 121

c d 122

d d 123

d d 124

b d 125

b c 126

c d 127

c b 128

c c Activity a: IC50 ≤ 100 nM b: 100 nM < IC50 ≤ 500 nM c: 500 nM < IC50≤ 1000 nM d: 1000 nM < IC50 ≤ 2200 nM Selectivity a: selectivity ≥ 100fold b: 100 fold > selectivity ≥ 50 fold c: 50 fold > selectivity ≥ 10fold d: 10 fold > selectivity

Pharmaceutical formulations can be administered in the form of dosageunits, which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using aprocess, which is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medica-ment after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone,a dissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting moulds. The lubricated mixture isthen pressed to give tablets. The active ingredients can also becombined with a free-flowing inert excipient and then pressed directlyto give tablets without carrying out the granulation or dry-pressingsteps. A transparent or opaque protective layer consisting of a shellacsealing layer, a layer of sugar or polymer material and a gloss layer ofwax may be present. Dyes can be added to these coatings in order to beable to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compounds. Syrups can be prepared bydissolving the compounds in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be for-mulated by dispersion of the compounds in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula (I) and salts, solvates and physiologicallyfunctional derivatives thereof and the other active ingredients can alsobe administered in the form of liposome delivery systems, such as, forexam-ple, small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidylcholines.

The compounds of the formula (I) and the salts, solvates andphysiologically functional derivatives thereof and the other activeingredients can also be delivered using monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds can also be coupled to soluble polymers as targeted medicamentcarriers. Such polymers may encompass polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropyl-methacrylamidophenol,polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-caprolactone, polyhydroxybutyric acid,poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base.

Alternatively, the active ingredient can be formulated to give a creamwith an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsus-pended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsuf-flators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula I and ofthe other active ingredient depends on a number of factors, including,for example, the age and weight of the animal, the precise diseasecondition which requires treatment, and its severity, the nature of theformulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound is generally in the range from 0.1 to 100 mg/kg of bodyweight of the recipient (mammal) per day and particularly typically inthe range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as an individual doseper day or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound per se.

Formulation 1—Tablets:

A compound of formula (I) is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 240-270 mgtablets (80-90 mg of active compound according to the invention pertablet) in a tablet press.

Formulation 2—Capsules:

A compound of formula (I) is admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of active compound according to the inventionper capsule).

Formulation 3—Liquid:

A compound of formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixedwith a previously prepared solution of microcrystalline cellulose andsodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate(10 mg), flavor, and color are diluted with water and added withstirring. Sufficient water is then added to produce a total volume of 5mL.

Formulation 4—Tablets:

A compound of formula (I) is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 450-900 mgtablets (150-300 mg of active compound according to the invention) in atablet press.

Formulation 5—Injection:

A compound of formula (I) is dissolved in a buffered sterile salineinjectable aqueous medium to a concentration of approximately 5 mg/mL.

1-12. (canceled)
 13. A compound of Formula (I)

wherein X denotes S, U is selected from (i) a phenyl ring which may besubstituted by 1 or 2 groups independently selected from C₁-C₆-alkoxy,C₁-C₆-alkyl, halogen, and CN; and (ii) a single bond; T denotes —NR⁵CO—,—CONR⁵, or —CO—; W is selected from

or the group W-A is selected from

each R⁵ is independently H or a linear or branched C₁-C₆-alkyl, R¹denotes a linear or branched alkyl having 1 to 6 carbon atoms; R^(a)denotes H, CN, halogen, a linear or branched alkyl having 1 to 6 carbonatoms, wherein 1 to 3 H atoms may be replaced by halogens, or linear orbranched alkoxy having 1 to 6 carbon atoms, wherein 1 to 3 H atoms maybe replaced by halogens, R², R³, R⁴ are each independently selected fromCN, halogen, a linear or branched alkyl having 1 to 6 carbon atoms,wherein 1 to 3 H atoms may be replaced by halogens, and linear orbranched alkoxy having 1 to 6 carbon atoms, wherein 1 to 3 H atoms maybe replaced by halogens, and a pharmaceutically acceptable salt,stereoisomer, or mixture thereof, in all ratios.
 14. The compoundaccording to claim 13 wherein U is a single bond or one of the followinggroups:


15. The compound according to claim 13 wherein the compound is selectedfrom: Ex. No Structure 93

94

105

108

109

110

112

113

114

115

116

117

118

119

120

121

122

123

124

125

127


16. A pharmaceutical composition comprising at least one compoundaccording to claim 13 and a pharmaceutically acceptable excipient.
 17. Amethod for the treatment or prevention of neurodegenerative diseases andrelated diseases, comprising administering to a subject a compound ofclaim 13, and pharmaceutically acceptable derivatives, solvates,tautomers, salts, hydrates and stereoisomers thereof, including mixturesthereof in all ratios.
 18. The method according to claim 17, wherein theneurodegenerative disease is selected from Alzheimer's disease, mildcognitive impairment, cerebral amyloid angiopathy and Down's Syndrome.